Adjuvant radiotherapy after radical prostatectomy: indications, results and side effects

BACKGROUND: Within 5 years following radical prostatectomy, between 15 and 60% of patients with pT3 prostate carcinomas show an increasing prostate-specific antigen (PSA) level as a sign of local and/or systemic tumor progression. Apart from a large number of retrospective investigations, available results are present only from three randomized studies which have either been completely published or are only in abstract form. RESULTS: For pT3 prostate carcinomas the data from the three randomized studies agree, showing an around 20% reduced biochemical progression rate after 4-5 years. With these data the results of numerous retrospective studies have been confirmed. The majority of the authors use total doses of 60 Gy with single doses of 2 Gy. From one randomized study an increased local control rate is proposed as the basis for the extended freedom from biochemical progression. The rate of acute and late side effects after three-dimensional radiotherapy with 60 Gy is very small and the rate of severe side effects is below 2%. The data for pT2 prostate carcinomas with positive margins are worse. Here controversy exists, and further investigations are required. In principle, however, adjuvant radiotherapy seems reasonable also for pT2 carcinomas with positive margins (determined by bNED - no biochemical evidence of disease). CONCLUSIONS: The effectiveness of adjuvant radiotherapy for patients with pT3 tumors and positive margins with and without detectable PSA levels is discussed. A survival advantage has not been demonstrated to date. For patients with positive margins in organ-limited prostate carcinomas (pT2 R1) randomized studies are recommended. It is unclear whether adjuvant radiotherapy is superior to radiotherapy for PSA levels increasing from the undetectable range after radical prostatectomy. To answer this question randomized studies are needed.     

pT3R1-Prostatakarzinom

Approximately 50-60% of patients with tumor stage pT3R1 after radical prostatectomy (RP) who do not receive adjuvant therapy develop biochemical progression. At present it is unclear whether these patients should undergo immediate adjuvant irradiation or whether a wait and see approach should be adopted while monitoring PSA until the PSA level rises from zero and then initiate salvage radiotherapy (SRT).Three randomized trials showed that an absolute improvement of 20% in the 5-year biochemical no evidence of disease (bNED) could be achieved by administering adjuvant radiotherapy with 60 Gy in patients with tumor stage pT3R1, even with a PSA level around zero after RP. The rate of serious late effects is low. On the other hand, there are numerous, albeit retrospective studies, which provide evidence that SRT after an increase in PSA above zero is an effective treatment, but with higher total doses of 66-70 Gy and a higher rate of late effects. Prognostic factors such as the PSA level before radiotherapy is started, PSA doubling time, R1 resection, PSA velocity, and the Gleason score have a significant impact on both the return of the PSA level to zero and the bNED. Depending on the risk factor, between 20 and 70% of patients again achieve PSA levels around zero after SRT. Retrospective comparative studies suggest a benefit of adjuvant radiotherapy; prospective randomized trials do not exist.Adjuvant radiotherapy after RP in stage pT3R1 tumor and SRT in cases of PSA rising above zero or persistent PSA levels are valid options for the management of high-risk patients after RP. SRT requires higher total doses and thus carries a higher risk of late complications. A benefit has been demonstrated for bNED, but not for survival. The approach should be discussed with the individual patient.     

ROLE OF EARLY ADJUVANT HORMONAL THERAPY AFTER RADICAL PROSTATECTOMY FOR PROSTATE CANCER

PURPOSE: Recent prospective randomized studies have shown that adjuvant hormonal therapy combined with local treatment can significantly improve overall survival in patients with locally advanced disease. This finding challenges the previous belief that adjuvant hormonal therapy may not be beneficial for minimal stages TxN + M0 or less prostate cancer, particularly when combined with local treatment. We reviewed the benefits of adjuvant hormonal therapy in patients at risk for disease progression, especially when administered after radical prostatectomy. MATERIALS AND METHODS: We retrospectively reviewed the current literature and evaluated clinical information on stage pT3b cancer from a large single institution prostate cancer database to determine the current role of adjuvant hormonal therapy after radical prostatectomy for prostate cancer. RESULTS: Retrospective experimental and clinical studies have proved the impact of adjuvant hormonal therapy for decreasing prostate specific antigen (PSA) and clinical disease progression in patients with regionally limited prostatic cancer. This finding applies to stage pT3b as well as to lymph node positive cancer. Our literature review and current data from the Mayo Clinic database show that adjuvant hormonal therapy after prostatectomy has a significant impact on prostate specific antigen (PSA) progression but it also decreases systemic progression and cause specific death in patients with stage pT3b and lymph node positive disease. After adjusting for preoperative PSA, margins, grade, ploidy and patient age the risk ratio for stage pT3b disease in 707 cases was 0.3 (95% confidence interval 0.2 to 0.7). A recent prospective randomized trial showed a significant decrease in cancer death in N+ cases when adjuvant hormonal therapy was administered after radical prostatectomy, supporting previous Mayo Clinic data on N+ disease that favors combination therapy. In the PSA era, that is 1987 and after, our database data on stage pTxN+ cancer indicates that radical prostatectomy and hormonal therapy for single node positive disease resulted in 94% 10-year cause specific survival, which was not significantly different from the rate in patients with N0 disease after adjusting for local stage, Gleason grade, margins, ploidy, PSA and adjuvant hormonal therapy. CONCLUSIONS: Our literature review, including prospective randomized studies, and more recent results in the PSA era from our database indicate that early adjuvant hormonal therapy has a significant impact on time to progression and cause specific survival in patients with seminal vesicle invasion and limited lymph node disease who undergo radical prostatectomy, although in a retrospective nonrandomized study. Future prospective studies with longer followup are needed to evaluate the potential benefit of adjuvant treatment in regard to survival for stages pT2 and pT3a disease with unfavorable pathological variables.     

Identification of factors predicting response to adjuvant radiation therapy in patients with positive margins after radical prostatectomy

PURPOSE: Radical prostatectomy (RP) is a highly effective treatment for patients with prostate cancer. However, patients with positive surgical margins after radical prostatectomy have less than ideal outcomes with 5-year progression rates between 36% and 50%. Postoperative radiation therapy (RT) is often advocated for improving these outcomes. We identified predictors of response to adjuvant RT given for positive margins after RP. MATERIALS AND METHODS: We retrospectively reviewed the clinical records of men who underwent RP between 1987 and 1999 at our institution and who received adjuvant RT for positive surgical margins. Only patients in whom prostate specific antigen (PSA) was undetectable after RP as well as before the initiation of RT were included. Numerous clinicopathological variables, including pre-RP PSA, pathological stage, margin length and location, and extracapsular extension or seminal vesicle involvement, were assessed for their adverse effect on the biochemical recurrence rate after adjuvant RT. RESULTS: A total of 62 men met our inclusion criteria. Median age at surgery was 60.7 +/- 6.1 years and median PSA at presentation was 9.0 ng/ml (range 1.4 to 64.9). The median RT dose was 60.0 +/- 3.6 Gy. RT was started a median of 5.0 +/- 3.6 months after RP. The 5 and 10-year biochemical disease-free survival rates for the whole group were 90.2% and 87.9%, respectively. Of all parameters tested only Gleason score 4 + 3 or greater (p = 0.037) and pre-RP PSA greater than 10.9 ng/ml (p = 0.040) were predictive of biochemical recurrence after adjuvant RT on univariate analysis. On multivariate analysis only pre-RP PSA greater than 10.9 ng/ml remained an independent predictor (p = 0.031). CONCLUSIONS: In the setting of true adjuvant RT in patients with positive margins after RP and undetectable PSA those with predominant Gleason grade 4 or greater, or PSA greater than 10.9 ng/ml at presentation are at increased risk for recurrence after adjuvant RT.     

Re: identification of patients with prostate cancer who benefit from immediate postoperative radiotherapy: EORTC 22911

In EORTC22911, 1005 patients with pT3 prostate cancer following radical prostatectomy were randomized to observation or immediate postoperative adjuvant radiotherapy [1]. Van der Kwast performed a pathologic analysis of EORTC22911 using the radical prostatectomy specimens from 552 study patients. Patients with negative surgical margins had no benefit from postoperative radiotherapy. However, with positive margins, the hazard ratio for prostate-specific antigen (PSA) relapse was 0.38 for those receiving radiation compared with those who did not. Adjuvant radiation would prevent biochemical relapse by year 5 in 291 of every 1000 patients with positive margins compared with 88 of 1000 patients with negative margins.     

Laparoscopic radical prostatectomy: oncological evaluation after 1,000 cases a Montsouris Institute

PURPOSE: We performed a prospective oncological evaluation of laparoscopic radical prostatectomy in regard to local tumor control and biochemical recurrence. MATERIALS AND METHODS: Between January 1998 and March 2002, 1,000 consecutive patients with a mean age +/- SD of 63 +/- 6.2 years and clinically localized prostate cancer underwent laparoscopic radical prostatectomy at 1 institution. Preoperative 1997 TNM clinical stage was T1a in 6 patients (0.6%), T1b in 3 (0.3%), T1c in 660 (66.5%), T2a in 304 (30.4%) and T2b in 27 (2.7%). Mean preoperative prostate specific antigen (PSA) +/- SD was 10 +/- 6.1 ng./ml. (range 1.5 to 55). Postoperatively, surgical specimens were assessed and positive surgical margins recorded. Factors that could influence the surgical margins status were evaluated. Irrespective of pathological stage or surgical margin status, no adjuvant treatment was proposed before an increasing PSA. PSA recurrence was defined as PSA greater than 0.1 ng./ml. and was confirmed by a second increase. Recurrence time was defined as the time of the first increase in PSA. RESULTS: Postoperative pathological stage was pT2aN0/Nx in 203 patients (20.3%), pT2bN0/Nx in 572 (57.2%), pT3aN0/Nx in 142 (14.2%), pT3bN0/Nx in 77 (7.7%) and pT1-3 N1 in 6 (0.6%). Positive surgical margin rate was 6.9%, 18.6%, 30% and 34% for pathological stages pT2a, pT2b, pT3a and pT3b, respectively (p <0.001). The main predictors of a positive surgical margin were preoperative PSA (p <0.001), clinical stage (p = 0.001), pathological stage (p <0.001) and Gleason score (p = 0.003). The overall actuarial biochemical progression-free survival rate was 90.5% at 3 years. According to the pathological stage, the progression-free survival rate was 91.8% for pT2aN0/Nx, 88% for pT2bN0/Nx, 77% for pT3aN0/Nx, 44% for pT3bN0/Nx and 50% for pT1-3N1 (p <0.001). Of the patients 94% with negative surgical margins and 80% with positive margins had progression-free survival (p <0.001). Preservation of the neurovascular bundles in patients with localized tumors had no significant effect on the subsequent risk of positive surgical margins or progression-free survival. CONCLUSIONS: Based on followup, our evaluation confirms that laparoscopic radical prostatectomy provides satisfactory results in regard to local tumor control and biochemical recurrence.     

Percutaneous radiotherapy for low-risk prostate cancer: options for 2007

Technical developments of radiotherapy (RT) over the recent years yielded in better conformation to the target volume thus increasing the therapeutic ratio and decreasing side effects. This paper discusses these options for low-risk prostate cancer. There has been evidence from randomized trials, that for low-risk PCA doses >70 Gy are significant better in case of biochemical disease-free survival (bNED). Image-guided radiotherapy (IGRT) has been proven in several studies for reduced safety margins around the prostate target volume. Intensity-modulated radiotherapy (IMRT) allow treatment with higher doses and 5-year results are reported from several studies. Data from several randomized trials about adjuvant RT after radical prostatectomy (RP) have been reported. In two phase-III trials a significant advantage of 20% bNED was demonstrated for doses between 76 and 79 Gy compared with 70 Gy. Using IGRT, the safety margin around the prostate can be reduced for about 30–50%. Doses of >80 Gy can be given safely to the prostate with IMRT and <5% grade-III/IV late side effects. Adjuvant RT for positive margins after RP has been of proven advantage. Three phase-III trials achieved a significant better bNED of 20% for 5 years. The effect of doses >70 Gy have been proven for low-risk PCA. IGRT resulted in reduced safety margins and a decrease of acute and late side effects. The addition of IMRT allowed higher doses to the prostate. Adjuvant RT after RP for positive margins achieved a significant better bNED.     

Organbegrenztes Prostatakarzinom mit positivem Resektionsrand

For pT3 prostate cancer with positive resection margins, the importance of postoperative radiation therapy is confirmed by a high level of evidence. However, for the pT2,R1 situation prospective, randomized studies concerning this question are lacking. Despite better local tumor control in the pT2 stage the PSA recurrence rate lies between 25% and 40% and positive margins are an independent factor for recurrence. Retrospective studies suggest a positive effect of adjuvant or salvage radiation for the oncological outcome in the pT2,R1 situation. On the other hand the side effects profile, with a potentially negative influence of postoperative continence and various delayed toxicities, is not insignificant despite modern radiation techniques and in the era of ultrasensitive PSA analysis should be considered in the risk-benefit assessment. As long as the optimal initiation of postoperative radiation therapy is unclear, the assessment of indications for adjuvant or salvage radiation for organ-limited prostate cancer with positive resection margins should be made after an individual patient consultation and under consideration of the recurrence risk factors, such as the Gleason grade and the localization and extent of the resection margins.     

Durable efficacy of early postoperative radiation therapy for high-risk pT3N0 prostate cancer: the importance of radiation dose

Objectives. To determine the durable efficacy of early postoperative radiation therapy (RT) in patients with pT3N0 prostate cancer who were at an increased risk of biochemical failure. We also evaluated the long-term benefit derived from using higher RT doses.Methods. Seventy-nine patients with pathologic Stage T3N0 prostate cancer and high-risk postoperative features underwent RT within 6 months after surgery. No patient received prior hormonal therapy. Fifty-nine patients had positive surgical margin, 29 had pathologic seminal vesicle invasion, and 27 had persistently elevated postoperative prostate-specific antigen (PSA) levels. Freedom from biochemical relapse (bNED) was defined as an undetectable (less than 0.2 ng/mL) PSA level. Median follow-up time was 39 months, and the median radiation dose was 64.8 Gy. All patients were followed for at least 2 years to be considered biochemically controlled.Results. Patients receiving adjuvant RT for an undetectable pre-RT PSA level had a 3-year bNED rate of 90%, compared with 44% for those receiving salvage RT for a detectable level (P < 0.0001). In the group of adjuvant patients, RT doses more than 61.2 Gy resulted in a 3-year bNED rate of 90% compared with 64% for those receiving a lower dose (P = 0.015). The salvage patients irradiated with a dose of 64.8 Gy or greater had a 3-year bNED rate of 52% compared with 18% for those irradiated with lower doses (P = 0.048). Severe late RT-related complications were infrequent and did not correlate with dose.Conclusions. In patients with high-risk pT3N0 prostate cancer, an RT dose response may exist. Although some studies suggest limited durable efficacy for early postoperative RT, our data suggest that RT doses of 64.8 Gy or more appear superior to prevent future biochemical failures. A prospective randomized study evaluating a postoperative RT dose response is warranted.     

What is to be done if the margin of resection is positive after radical prostatectomy?

Summary In the last years radical retropubic prostatectomy has become the treatment of choice for locally confined prostate cancer (PCa). However, in the literature local recurrence is described in 4–23 % of patients with clinical stage T1–2 prostate cancer and in 43 % of patients with clinical stage T3 respectively. The problem is further aggravated that postoperatively raised PSA values are detected in 6–8 % of patients with locally confined prostate cancer indicating either local residual tumor or systemic disease. Current datas show that wait-and-watch appears to be the best option for patients with locally confined prostate cancer and positive margins. In case of persistent or raising PSA-values following prostatectomy without detectable local recurrence or metastasis mere local therapy cannot be recommended. Primary radiotherapy should be considered in cases with confirmed clinical local recurrence without distant metastasis. Further prospective and randomized trials have to be initiated to identify the patients with positive margins who will benefit from adjuvant treatment.      

Adjuvant versus salvage radiation therapy for prostate cancer and the risk of death

Study Type – Therapy (case series)
Level of Evidence 4

OBJECTIVE

To investigate whether salvage radiation therapy (RT) for prostate‐specific antigen (PSA) failure can provide the same result as adjuvant RT, which decreases the risk of all‐cause mortality (ACM) for men with positive margins (R1), or extra‐capsular or seminal vesicle extension (pT3).

METHODS

We studied 1638 men at Duke University who underwent radical prostatectomy for unfavourable‐risk prostate cancer and whose postoperative PSA was undetectable. Cox regression was used to evaluate whether salvage vs adjuvant RT in men with a rapid (<10 months) or slow (≥10 months) PSA doubling time (DT) was associated with the risk of ACM, adjusting for adverse features (pT3, R1, Gleason score 8–10), age, preoperative PSA level, comorbidity and hormonal therapy use.

RESULTS

Despite fewer men with two or more adverse features (61 vs 82%; P = 0.016), salvage for a rapid PSA DT vs adjuvant RT increased the risk of ACM [adjusted hazard ratio (AHR) = 3.42; 95% confidence interval (CI) = 1.27–9.20; P = 0.015]. There was no difference (AHR = 1.39; 95% CI = 0.50–3.90; P = 0.53) in the risk of ACM among men who received salvage for a slow PSA DT or adjuvant RT. Nearly all (90%) men with a slow PSA DT had Gleason score ≤7 and the majority (59%) had at most pT3 or R1 disease.

CONCLUSION

Radiation therapy after PSA failure as compared with adjuvant RT was not associated with an increased risk of ACM in men with Gleason score ≤7 and pT3R0 or pT2R1 disease.     

pT3 Prostate Cancer: The Case for Salvage (as Opposed to Adjuvant) Radiation Therapy

ObjectivesIt is unclear as yet whether or not adjuvant treatment for radical prostatectomy achieves better oncologic results than early salvage treatment.MethodsThree recently published randomized clinical trials have shown that adjuvant radiation therapy (ART) for pT3 prostate cancer with or without positive surgical margins (PSMs) and seminal vesicle invasion (SVI) is associated with a 25–30% improvement in biochemical and clinical relapse-free survival; however, this was not translated into a significant improvement in metastatic-free and overall survival.ResultsRecent studies have shown that salvage radiation therapy (SRT) given at very low levels of prostate-specific antigen (0.5–1 ng/ml) is probably as efficient as adjuvant radiation therapy given to everyone in terms of biochemical-free survival.ConclusionsA plea is made for a more selective and individualized use of radiation therapy in prostate cancer patients with pT3 disease.     

Radical prostatectomy can provide a cure for well-selected clinical stage T3 prostate cancer

OBJECTIVE: Radical prostatectomy is commonly believed not to achieve the eradication of locally advanced disease. This retrospective study aimed to elucidate the role of radical prostatectomy in this condition. METHODS: A retrospective study of 158 patients surgically treated for clinical stage T3N0M0 prostate cancer was undertaken. Thirty patients had postoperative hormonal treatment, rendering prostate-specific antigen (PSA) follow-up unreliable, and were considered to be progressive at 1 month. Eighteen other patients received postoperative radiotherapy. One hundred and ten patients had radical prostatectomy only. PSA-relapse-free survival was analyzed. The mean follow-up time was 30 months. RESULTS: Seventy-nine percent of the resected specimens were pathologically T3 (pT3), and about 25% were pT3c. Thirteen percent were pT2 and 8% were pT4. Ninety-five specimens (60%) had positive surgical margins. There was poor accordance between the biopsy Gleason score and that of the specimen. A multivariate analysis showed that seminal vesicle and nodal invasion, margin status and a PSA level above 10 ng/ml were independent prognostic factors. In 47 cT3a patients with PSA <10 ng/ml, the PSA-free survival rate exceeded 70% at 24 months and the 5-year estimated PSA-free survival rate was more than 60%. CONCLUSIONS: Radical prostatectomy has a place in the treatment of clinical stage T3 prostate cancer patients with a PSA value lower than 10 ng/ml. There is a need to definitively rule out nodal or seminal vesicle invasion in order to select those patients that can benefit from surgery.     

Neoadjuvant hormonal therapy in carcinoma of the prostate

The rising incidence of and mortality from prostate cancer has generated great interest in improving the results of current methods of treatment. It is well-established that large tumour volumes and positive surgical margins are correlated with higher rates of local failure and distant metastasis. Significant decreases in both tumour volume and the rates of positive surgical margins are seen with NHT. Follow-up data from one randomized trial of hormonal therapy before RT have shown significantly improved disease-free survival, but so far there has been no benefit in overall survival. However, the addition of adjuvant hormonal therapy has been reported to improve survival. The results suggest that neoadjuvant and adjuvant hormonal therapy may be a viable option in men with locally advanced prostate cancer in whom cure is probably impossible, but disease progression can potentially be slowed. What remains to be determined is whether hormonal therapy alone can produce the same results. For younger men with clinically localized prostate cancer, radical prostatectomy is increasingly the treatment of choice. Prospective randomized trials of NHT have produced impressive statistics for decreasing the incidence of positive surgical margins, but the potential to down-stage tumours remains controversial. Follow-up serum PSA measurements have thus far shown no benefit from neoadjuvant therapy. The possibility that patients who fail biochemically, whether they are from the pretreated or control group, may simply represent a subgroup with aggressive tumours that may not respond to androgen withdrawal, has yet to be proved. As more follow-up data are analysed within the next several years, there must be a clear survival advantage if NHT is to be offered as a treatment option. Despite the potential of neoadjuvant therapy, the use of androgen withdrawal before definitive surgical treatment should be limited to clinical trials until a clearer picture emerges. Some may argue that although there is no evidence of a true advantage for NHT, neither is there evidence of harm. However, it must be recognized that androgen withdrawal therapy has side-effects and adds significantly to the overall cost of treatment. Furthermore, NHT delays definitive treatment; clearly, this can be a source of anxiety for the patient and the impact on survival is unknown. Currently, the rates of pathologically organ-confined disease are high in some subsets of patients (e.g. low-stage, low-grade and low PSA) so that NHT is unlikely to have great additional benefit. Although the influence of hormones on prostate growth has been known for many decades, we are only now elucidating the biological mechanisms of hormonal therapy. Although androgen ablation therapy has been used in men with metastatic prostate cancer for more than 50 years, further research at the cellular and molecular level is essential if we are to refine treatment modalities for both localized and advanced disease. Furthermore, until we have more follow-up data from randomized clinical trials of NHT, it cannot be considered part of the standard treatment for carcinoma of the prostate. There are still too many unknown factors; only time will tell if the initial promise of NHT will be fulfilled.     

Comparison of surgery alone with surgery and adjuvant radiotherapy for pT3N0 prostate cancer

OBJECTIVE: To compare the outcome between patients with pT3N0 adenocarcinoma of the prostate treated with radical prostatectomy (RP) and those receiving RP followed by a planned course of postoperative radiation therapy (RT). PATIENTS AND METHODS: During a period of 22 years 622 patients with pT3N0 prostate cancer were treated in one medical centre by RP. Of these, 199 (32%) were treated with surgery alone while 423 (68%) received planned postoperative pelvic RT (median 48 Gy). Patients were selected for RT by having a higher incidence of adverse prognostic factors than those undergoing RP alone. These prognostic factors included pathological stage (P = 0.001) preoperative prostate specific antigen (PSA) level (P < 0.001) and Gleason score (P = 0.18). The patients' median age was 66 years; the median follow-up was 6.1 years for all patients, 7 years for RP + RT and 5 years for the RP-alone. RESULTS: The 5- and 10-year actuarial survival was 92% and 73%, respectively, for RP + RT patients, and nearly identical for those in the RP-alone group (P = 0.73). The 5- and 10-year disease-free survival (DFS; PSA < 0.05 ng/mL) was 69% and 51%, respectively, for the former, and 71% and 60%, respectively, for the latter group. There was no significant difference in DFS between the treatment groups by pathological stage and Gleason score (P = 0.77). Likewise, there was no significant difference in mean and median time to relapse. A preoperative PSA level of < 10 vs 10-25 vs > 25 ng/mL did not influence overall survival but a PSA of > 25 ng/mL was predictive of DFS (P = 0.02). In a multivariate analysis the Gleason score was the most important predictor for overall survival and DFS (P < 0.001), while pathological stage was predictive of clinical recurrence and DFS (P < 0.001). After controlling for pathological stage and Gleason score, RP + RT patients were predicted to recur at 92% of the rate of RP-alone patients (P = 0.65). In all, 43 (10%) patients developed a clinical recurrence in the RP + RT group, including 30 (7%) patients with distant metastases alone, 13 (3%) with local recurrence, with an additional 88 (21%) who had PSA recurrence (PSA > 0.05 ng/mL). This compared with 13 (6.5%) patients with clinical recurrence, including seven (3.5%) with local recurrence and 23 (11.6%) with PSA > 0.05 ng/mL in the RP-alone group. Postoperative RT was well tolerated and did not add to the incidence of surgical complications. CONCLUSION: We propose that postoperative RT, as described here, helped to reduce the incidence of local recurrence and improved DFS to equal that of a lower-risk group of patients treated with RP alone. A randomized comparison is needed to define the role of adjuvant RT in patients with pT3N0 disease.     

The ability of the American Joint Committee on Cancer Staging system to predict progression-free survival after radical prostatectomy

OBJECTIVE: To examine, in a retrospective analysis of outcome based on prostate-specific antigen (PSA) levels, whether the 1992 and revised 1997 staging criteria for prostate cancer can be used to predict progression-free survival for patients after radical prostatectomy for pT2 and pT3 prostate cancer. PATIENTS AND METHODS: In all, 291 patients with a PSA determination during a 6-month interval after radical prostatectomy were analysed (mean follow-up 5.2 years). In the absence of a uniform system of pathological staging, the histopathological stage was defined according to the 1992 and 1997 American Joint Cancer Committee/Union Internationale Contre le Cancer (AJCC/UICC) tumour-nodes-metastases (TNM) staging classification. Findings were correlated with the PSA value after surgery. The subgroups of pT2 and pT3 disease were compared for the time to PSA progression, using Kaplan-Meier data analysis and the log-rank test. RESULTS: The biochemical progression-free 5-year survival rates for stage pT2 were 83% (pT2a), 81% (pT2b) and 62% (pT2c); there were no significant differences in the pT2 subgroups. The recurrence-free rates for pT3 were 79% (pT3a), 65% (pT3b) and 50% (pT3c); the actuarial recurrence-free rate was significantly different for patients with 1997 AJCC pT3a vs pT3b disease (P=0.0132). There was no significant difference in the 1992 AJCC stages pT2a vs pT2b (P=0.1232) and the recurrence-free rate was not significantly different for patients with 1992 AJCC pT3a vs pT3b disease (P=0.9). There was a significant difference in the likelihood of a PSA relapse between patients with positive and negative surgical margins (P=0.131). CONCLUSION: These results support the current revised 1997 AJCC/UICC staging system for prostate cancer. There is an urgent need to develop a pathological equivalent to the AJCC/UIC TNM clinical staging system. Greater clinical input and evaluation from different institutions are essential to reach consensus on pathological staging categories that maximize the predictability of outcome after definitive therapy. Crucial issues are the definition and quantification of extraprostatic extension and definition of surgical margin categories.     

Prognostic significance of tumor volume after radical prostatectomy: a multivariate analysis of pathological prognostic factors

OBJECTIVES: To analyze the association between Gleason score, stage and status of surgical margins with tumor volume in prostate cancer progression after radical prostatectomy. METHODS: 200 consecutive radical prostatectomy specimens were analyzed. Preoperative clinical stage, PSA, results of prostate biopsies as well as pathological results were noted. A biochemical recurrence was defined as a single, postoperative detectable PSA level (>0.2 ng/ml). Tumor volume was compared to postoperative staging, Gleason score, and surgical margin status to predict tumor progression. Univariate and multivariate analysis using stepwise logistic regression were used to identify parameters with additional prognostic value. RESULTS: Pathological results of the prostatectomy specimens showed 149 (74.5%) pT2a-b, 29 (14.5%) pT3a and 22 (11%) pT3b tumors. Tumor volume was 0.57 cc for pT2a, 1.2cc for pT2b, 1.7cc for pT3a and 2.9cc for pT3b, respectively (p<0.05). Taken together, mean volume for pT2 and pT3 were 1.06 and 2.2 cc, respectively (p<0.0001). Five-year progression-free actuarial survival was 69.7%. Using univariate analysis, tumor progression correlated with final Gleason score (p<0.0007), positive surgical margins (p=0.02), tumor volume (p=0.009) and stage (p<0.0001). In a multivariate analysis, tumor progression correlated only with the final Gleason score (p=0.04) and stage (p=0.0002). CONCLUSION: Gleason score and pathological stage are independent factors to predict prostate cancer progression after radical prostatectomy. When these parameters are known, tumor volume does not provide additional information.     

Laparoscopic radical prostatectomy: is intact organ removal attainable? Study of margin status

PURPOSE: To determine the initial oncologic results (pathology) of specimens removed by laparoscopic radical prostatectomy (LRP) by examining the surgical margins. PATIENTS AND METHODS: The 70 consecutive LRP procedures performed for clinically localized prostate cancer at Eastern Virginia Medical School from April 2001 to November 2002 were reviewed for preoperative and important intraoperative variables. The initial histopathology report and a prospective review by a single genitourinary pathologist for margin status as well parenchymal exposure of benign glands were assessed. Postoperative prostate specific antigen (PSA) levels were noted. RESULTS: The clinical stage distribution was as follows: T1c = 59, T2a = 10, and T2b = 1. The preoperative median PSA value was 6.96 ng/mL. The mean operative time was 307 minutes. The mean estimated blood loss was 298 mL. The prospective pathologic review results were as follows: 1 pT0 (1.4%), 60 pT2 (85.7%), and 9 pT3 (12.8%). The overall positive surgical-margin rate was 15.7%. Of those patients with pT2 disease; 8 specimens (13.3%) had a positive margin, whereas 33% of patients with pT3 disease had a positive surgical margin. Parenchymal exposure of benign glands on the inked surface was recognized in 8 patients (13.3%). Data from PSA assays 1 month postoperatively were available in 69 patients. Serum PSA was undetectable (< or =0.1 ng/mL) in 67 men (97%). CONCLUSION: An LRP can offer surgical margins comparable to those of open procedures series reported in the literature. Long-term progression and survival outcome data are necessary before this procedure should be offered as a replacement for open prostatectomy.     

Postoperative radiotherapy after prostatectomy--a review

PURPOSE: The management of prostate adenocarcinomas using postoperative irradiation is a controversial question. The purpose of this study was to review the literature on the subject. MATERIAL AND METHODS: A total of 417 articles dealing with postoperative radiotherapy after radical prostatectomy in English literature (1990-2002) were reviewed in aspects of effect on survival, time of irradiation, risk factors, dose and technique and side effects. RESULTS AND DISCUSSION: No randomised studies have been performed and therefore no definitive conclusive data can be made concerning the efficiency of the concept. However, postoperative radiotherapy appears to increase local control preferably in pT3/4 prostatic carcinomas with seminal vesicles involvement and/or positive margins and/or high Gleason score and high postoperative PSA level. It has not been shown to improve survival. Severe side effects are reported in a low frequency. However, postoperative irradiation can cause severe side effects and postoperative adjuvant/salvage treatments should be delivered earliest 3-6 months after surgery and the total dose delivered to the prostate bed should be 65-70 Gy. Postoperative radiotherapy induces improved local control in patients with positive surgical margins and in patients with a local relapse, preferably if the tumour is small (i.e. PSA <1-2 ng/mL).     

Postoperative radiation therapy for pathologically advanced prostate cancer after radical prostatectomy

Context

Approximately 15-25% of men who undergo radical prostatectomy for localized prostate cancer (PCa) will experience recurrence of their cancer; men with poorly differentiated cancer, non-organ-confined disease, and positive surgical margins are at the highest risk.

Objective

Review accumulating evidence indicating that postoperative radiotherapy (RT) to the prostate bed favorably influences the course of disease in men with adverse pathologic features.

Evidence acquisition

Three phase 3 randomized trials of adjuvant RT versus observation have reported improved freedom from biochemical recurrence (BCR) and local control: Southwest Oncology Group (SWOG) 8794, European Organization for Research and Treatment of Cancer (EORTC) 22911, and the German Cancer Society (ARO 96-02).

Evidence synthesis

Conflicting evidence from these trials suggests that adjuvant RT can have a favorable impact on systemic progression, PCa-specific mortality, or overall survival. Observational studies have reported durable responses to salvage RT in a substantial proportion of high-risk patients (provided that it is administered at the earliest evidence of BCR) and reduced PCa-specific mortality. There is consensus that the outcome of patients receiving postoperative RT is best when the prostate-specific antigen (PSA) level is the lowest. However, it is unclear if better outcomes will be achieved administering adjuvant RT to all patients at increased risk for recurrent PCa who have an undetectable postoperative PSA level compared to close observation and timely salvage RT at the earliest indications of BCR.

Conclusions

Given the absence of data from randomized trials demonstrating superiority of one approach over the other in terms of quantity and quality of life, we advocate multidisciplinary input and shared and informed decision making among patients, urologists, and radiation oncologists based on the relative advantages and disadvantages of each approach.