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Proposed prognostic scoring system evaluating risk factors for biochemical recurrence of prostate cancer after salvage radiation therapy
Abstract
To update a previously proposed prognostic scoring system that predicts risk of biochemical recurrence (BCR) after salvage radiation therapy (SRT) for recurrent prostate cancer when using additional patients and a PSA value of 0.2 ng/ml and rising as the definition of BCR.
We included 577 patients who received SRT for a rising PSA following radical prostatectomy in this retrospective cohort study. Clinical, pathological, and SRT characteristics were evaluated for association with BCR using relative risks (RRs) from multivariable Cox regression models.
With a median follow-up of 5.5 years following SRT, 354 patients (61%) experienced BCR. At 5 years following SRT, 40% of patients were free of BCR. Independent associations with BCR were identified for pre-SRT PSA (RR [doubling]: 1.25, P<0.001), pathological tumor stage (RR [T3a vs. T2]: 1.21, P=0.19; RR [T3b/T4 vs. T2]: 2.09, P<0.001; overall P<0.001), Gleason score (RR [7 vs. <7]: 1.63, P<0.001; RR [8-10 vs. <7]: 2.28, P<0.001; overall P<0.001), and surgical margin status (RR [positive vs. negative]: 0.71, P=0.003).We combined these 4 variables to create a prognostic scoring system that predicted BCR risk with a c-index of 0.66. Scores ranged from 0 to 7, and 5-year freedom from BCR for different levels of the score was as follows: Score=0-1: 66%, Score=2: 46%, Score=3: 28%, Score=4: 19%, and Score=5-7: 15%.
We developed a scoring system that provides an estimation of biochemical outcome after SRT. These findings will be useful for patients and physicians in decision making for radiation therapy in the salvage setting. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
... Of these, between 15% and 25% will experience a significant rise in their serum prostate specific antigen level following surgery, indicating a biochemical recurrence (BCR) of their disease [1]. The only potentially curative treatment option available to men who have experienced BCR of prostate cancer after RP is salvage radiation therapy (SRT); however, the reported success of SRT have ranged from 10% to 65% [2][3][4][5][6][7][8][9][10]. As such, the ability to accurately identify which men have the highest likelihood of responding to SRT represents a key clinical issue for the field. ...
... Related to this, a number of studies have been performed that attempt to identify specific characteristics that are associated with risk of BCR after SRT. Several well-replicated risk factors have been established, such as elevated pre-SRT PSA level, more advanced pathological tumor stage, higher Gleason score, negative surgical margin, and shorter pre-SRT PSA doubling time [2][3][4][5][6][7][8][9][10]. ...
... In an attempt to provide patients with individualized estimates of BCR risk that are tailored to their clinical and pathological characteristics, several large studies have proposed scoring algorithms that combine information from multiple prognostic factors [4][5]10]. However, the ability of these algorithms to stratify risk of BCR has considerable room for improvement; for example, a notable proportion of patients in the low BCR risks groups still experience BCR [4][5][8][9][10]. ...
Background
Standardly collected clinical and pathological patient information has demonstrated only moderate ability to predict risk of biochemical recurrence (BCR) of prostate cancer in men undergoing salvage radiation therapy (SRT) for a rising PSA after radical prostatectomy (RP). Although elevated FOXA1 staining has been associated with poor patient outcomes following RP, it has not been studied in the specific setting of SRT after RP. The aim of this study was to evaluate the association between FOXA1 staining level and BCR after SRT for recurrent prostate cancer.
Methods
A total of 141 men who underwent SRT at our institution were included. FOXA1 staining levels in primary tumor samples were detected using immunohistochemistry. FOXA1 staining percentage and intensity were measured and multiplied together to obtain a FOXA1 H-score (range 0–12) which was our primary staining measure. P-values ≤ 0.0056 were considered as statistically significant after applying a Bonferroni correction for multiple comparisons.
Results
There was not a significant association between FOXA1 H-score and risk of BCR when considering H-score as an ordinal variable or as a categorical variable (all P≥0.090). Similarly, no significant associations with BCR were observed for FOXA1 staining percentage or staining intensity (all P≥0.14).
Conclusions
FOXA1 staining level does not appear to have a major impact on risk of BCR after SRT.
... Smaller studies previously evaluated the expression of p53, Bcl-2 and Ki-67 [27][28][29]. Lee et al. developed a scoring system that provides an estimation risk of biochemical failure after salvage radiotherapy, based on PSA, pathological tumor stage, Gleason score and surgical margin status with a c-index of 0.66 [30]. ...
Prostate cancer (Pca) is among the most common malignant diseases in men and the fourth leading cause of death worldwide. Surgery and radical radiotherapy (RT) remain the gold standard for the treatment of localized or locally advanced prostate cancer. The efficiency of radiotherapy treatment is limited by toxic side effects due to dose escalation. Cancer cells often develop radio-resistant mechanisms that are related to the DNA repair, inhibition of apoptosis or changes in cell cycle. Based on our earlier research on biomarkers that are involved in those cellular mechanisms (p53, bcl-2, NF-kb, Cripto-1 and Ki67 proliferation) and correlation with clinico-pathological parameters (age, PSA value, Gleason score, grade group, prognostic group), we created the numerical index for risk of tumor progression in patients with radioresistant tumors. For each of these parameters, the strength of association with disease progression was statistically assessed, and a specific number of points was assigned proportional to the strength of the correlation. Statistical analysis identified an optimal cut-off score of 22 or more as an indicator of significant risk for progression with a sensitivity of 91.7% and a specificity of 66.7%. The scoring system in the retrospective receiver operating characteristic analysis showed AUC of 0.82. The potential value of this scoring is the possibility of identifying patients with clinically significant radioresistant Pca.
Objectives:
High GATA2 expression has been associated with an increased risk of poor clinical outcomes after radical prostatectomy (RP), however has not been studied in relation to risk of biochemical recurrence (BCR) after salvage radiation therapy (SRT) for recurrent prostate cancer after RP. Our aim was to evaluate the association between protein expression levels of GATA2 in primary prostate cancer tumor samples and risk of BCR after SRT.
Methods:
109 men who were treated with SRT were included. The percentage of cells with nuclear staining and GATA2 staining intensity were both measured. These two measures were multiplied together to obtain a GATA2 H-score (range 0-12) which was our primary GATA2 staining measure.
Results:
In unadjusted analysis, risk of BCR was higher for patients with a GATA2 H-score >4 (Hazard ratio=2.04, P=0.033). In multivariable analysis adjusting for SRT dose, pre-SRT PSA, pathological tumor stage, and Gleason score, this association weakened substantially (Hazard ratio=1.45, P=0.31). This lack of an independent association with BCR appears to be the result of correlations between GATA2 H-score >4 and higher pre-SRT PSA (P=0.021), higher Gleason score (P=0.044), and more severe pathological tumor stage (P=0.068).
Conclusions:
Higher levels of GATA2 expression appear to be a marker of prostate cancer severity, however do not provide independent prognostic information regarding BCR beyond that of validated clinico-pathologic risk factors. Advances in Knowledge: A higher GATA2 expression level appears to be correlated with known measures of prostate cancer severity and therefore is likely not an independent marker of outcome after SRT.
The ideal prostate-specific antigen (PSA) doubling time (PSADT) threshold for identifying patients at high-risk for poor clinical outcome following salvage radiation therapy (SRT) has not been well established. We sought to assess what PSADT threshold is most clinically prognostic in this setting.
575 patients who received SRT at a single institution for biochemical recurrence after radical prostatectomy were retrospectively reviewed. We assessed the impact of pre-SRT PSADT on biochemical failure (BF), distant metastasis (DM), prostate cancer-specific mortality (PCSM), and overall mortality (OM). Kaplan-Meier methods, hazard ratio (HR) assessment, and Cox Proportional Hazard models were used to assess the discriminatory ability of various PSADT thresholds.
Sufficient data to calculate PSADTs were available for 277 patients. PSADT was prognostic for BF, DM, PCSM, and OM on univariate analysis regardless of threshold. HR assessment identified 6 months as a strong threshold. No statistically significant difference was observed in BF, DM, PCSM, or OM between patients with PSADT <3 (n=40) and 3--6 months (n=61) or between 6--10 (n=62) and >10 months (n=114). However significant differences were seen in BF (HR:2.2, [95%CI: 1.4-3.5], p<0.01) and DM (HR:2.2, [95%CI: 1.2-4.3], p=0.02) between a PSADT of 3--6 and 6--10 months. On multivariate analysis a PSADT <6 months predicted BF (HR:2.0, [95%CI: 1.4-2.9], p=0.0001), DM (HR:2.0, [95%CI: 1.2-3.4], p=0.01), and PCSM (HR:2.6, [95%CI: 1.1-5.9], p=0.02).
A pre-SRT PSADT <6 months was a strong predictor of outcomes in our data set, including PCSM. The most common nomogram for SRT uses a 10-month PSADT threshold for assigning points used to assess BF following SRT. If validated, our findings suggest that a PSADT threshold of <6 months should be considered for stratification of patients in future clinical trials in this setting.
In 2008, we reported that radical prostatectomy, as compared with watchful waiting, reduces the rate of death from prostate cancer. After an additional 3 years of follow-up, we now report estimated 15-year results.
From October 1989 through February 1999, we randomly assigned 695 men with early prostate cancer to watchful waiting or radical prostatectomy. Follow-up was complete through December 2009, with histopathological review of biopsy and radical-prostatectomy specimens and blinded evaluation of causes of death. Relative risks, with 95% confidence intervals, were estimated with the use of a Cox proportional-hazards model.
During a median of 12.8 years, 166 of the 347 men in the radical-prostatectomy group and 201 of the 348 in the watchful-waiting group died (P=0.007). In the case of 55 men assigned to surgery and 81 men assigned to watchful waiting, death was due to prostate cancer. This yielded a cumulative incidence of death from prostate cancer at 15 years of 14.6% and 20.7%, respectively (a difference of 6.1 percentage points; 95% confidence interval [CI], 0.2 to 12.0), and a relative risk with surgery of 0.62 (95% CI, 0.44 to 0.87; P=0.01). The survival benefit was similar before and after 9 years of follow-up, was observed also among men with low-risk prostate cancer, and was confined to men younger than 65 years of age. The number needed to treat to avert one death was 15 overall and 7 for men younger than 65 years of age. Among men who underwent radical prostatectomy, those with extracapsular tumor growth had a risk of death from prostate cancer that was 7 times that of men without extracapsular tumor growth (relative risk, 6.9; 95% CI, 2.6 to 18.4).
Radical prostatectomy was associated with a reduction in the rate of death from prostate cancer. Men with extracapsular tumor growth may benefit from adjuvant local or systemic treatment. (Funded by the Swedish Cancer Society and the National Institutes of Health.).
The natural history of biochemical recurrence after radical prostatectomy can be long but variable. Better risk assessment models are needed to identify men who are at high risk for prostate cancer death early and who may benefit from aggressive salvage treatment and to identify men who are at low risk for prostate cancer death and can be safely observed.
To define risk factors for prostate cancer death following radical prostatectomy and to develop tables to risk stratify for prostate cancer-specific survival.
Retrospective cohort study of 379 men who had undergone radical prostatectomy at an urban tertiary care hospital between 1982 and 2000 and who had a biochemical recurrence and after biochemical failure had at least 2 prostate-specific antigen (PSA) values at least 3 months apart in order to calculate PSA doubling time (PSADT). The mean (SD) follow-up after surgery was 10.3 (4.7) years and median follow-up was 10 years (range, 1-20 years).
Prostate cancer-specific mortality.
Median survival had not been reached after 16 years of follow-up after biochemical recurrence. Prostate-specific doubling time (<3.0 vs 3.0-8.9 vs 9.0-14.9 vs > or =15.0 months), pathological Gleason score (< or =7 vs 8-10), and time from surgery to biochemical recurrence (< or =3 vs >3 years) were all significant risk factors for time to prostate-specific mortality. Using these 3 variables, tables were constructed to estimate the risk of prostate cancer-specific survival at year 15 after biochemical recurrence.
Clinical parameters (PSADT, pathological Gleason score, and time from surgery to biochemical recurrence) can help risk stratify patients for prostate cancer-specific mortality following biochemical recurrence after radical prostatectomy. These preliminary findings may serve as useful guides to patients and their physicians to identify patients at high risk for prostate cancer-specific mortality following biochemical recurrence after radical prostatectomy to enroll them in early aggressive treatment trials. In addition, these preliminary findings highlight that survival in low-risk patients can be quite prolonged.
An increasing serum prostate-specific antigen (PSA) level is the initial sign of recurrent prostate cancer among patients treated with radical prostatectomy. Salvage radiation therapy (SRT) may eradicate locally recurrent cancer, but studies to distinguish local from systemic recurrence lack adequate sensitivity and specificity. We developed a nomogram to predict the probability of cancer control at 6 years after SRT for PSA-defined recurrence.
Using multivariable Cox regression analysis, we constructed a model to predict the probability of disease progression after SRT in a multi-institutional cohort of 1,540 patients.
The 6-year progression-free probability was 32% (95% CI, 28% to 35%) overall. Forty-eight percent (95% CI, 40% to 56%) of patients treated with SRT alone at PSA levels of 0.50 ng/mL or lower were disease free at 6 years, including 41% (95% CI, 31% to 51%) who also had a PSA doubling time of 10 months or less or poorly differentiated (Gleason grade 8 to 10) cancer. Significant variables in the model were PSA level before SRT (P < .001), prostatectomy Gleason grade (P < .001), PSA doubling time (P < .001), surgical margins (P < .001), androgen-deprivation therapy before or during SRT (P < .001), and lymph node metastasis (P = .019). The resultant nomogram was internally validated and had a concordance index of 0.69.
Nearly half of patients with recurrent prostate cancer after radical prostatectomy have a long-term PSA response to SRT when treatment is administered at the earliest sign of recurrence. The nomogram we developed predicts the outcome of SRT and should prove valuable for medical decision making for patients with a rising PSA level.
Biochemical disease recurrence after radical prostatectomy often prompts salvage radiotherapy, but no studies to date have had sufficient numbers of patients or follow-up to determine whether radiotherapy improves survival, and if so, the subgroup of men most likely to benefit.
To quantify the relative improvement in prostate cancer-specific survival of salvage radiotherapy vs no therapy after biochemical recurrence following prostatectomy, and to identify subgroups for whom salvage treatment is most beneficial.
Retrospective analysis of a cohort of 635 US men undergoing prostatectomy from 1982-2004, followed up through December 28, 2007, who experienced biochemical and/or local recurrence and received no salvage treatment (n = 397), salvage radiotherapy alone (n = 160), or salvage radiotherapy combined with hormonal therapy (n = 78).
Prostate cancer-specific survival defined from time of recurrence until death from disease.
With a median follow-up of 6 years after recurrence and 9 years after prostatectomy, 116 men (18%) died from prostate cancer, including 89 (22%) who received no salvage treatment, 18 (11%) who received salvage radiotherapy alone, and 9 (12%) who received salvage radiotherapy and hormonal therapy. Salvage radiotherapy alone was associated with a significant 3-fold increase in prostate cancer-specific survival relative to those who received no salvage treatment (hazard ratio [HR], 0.32 [95% confidence interval {CI}, 0.19-0.54]; P<.001). Addition of hormonal therapy to salvage radiotherapy was not associated with any additional increase in prostate cancer-specific survival (HR, 0.34 [95% CI, 0.17-0.69]; P = .003). The increase in prostate cancer-specific survival associated with salvage radiotherapy was limited to men with a prostate-specific antigen doubling time of less than 6 months and remained after adjustment for pathological stage and other established prognostic factors. Salvage radiotherapy initiated more than 2 years after recurrence provided no significant increase in prostate cancer-specific survival. Men whose prostate-specific antigen level never became undetectable after salvage radiotherapy did not experience a significant increase in prostate cancer-specific survival. Salvage radiotherapy also was associated with a significant increase in overall survival.
Salvage radiotherapy administered within 2 years of biochemical recurrence was associated with a significant increase in prostate cancer-specific survival among men with a prostate-specific antigen doubling time of less than 6 months, independent of other prognostic features such as pathological stage or Gleason score. These preliminary findings should be validated in other settings, and ultimately, in a randomized controlled trial.
Multivariable regression models are powerful tools that are used frequently in studies of clinical outcomes. These models can use a mixture of categorical and continuous variables and can handle partially observed (censored) responses. However, uncritical application of modelling techniques can result in models that poorly fit the dataset at hand, or, even more likely, inaccurately predict outcomes on new subjects. One must know how to measure qualities of a model's fit in order to avoid poorly fitted or overfitted models. Measurement of predictive accuracy can be difficult for survival time data in the presence of censoring. We discuss an easily interpretable index of predictive discrimination as well as methods for assessing calibration of predicted survival probabilities. Both types of predictive accuracy should be unbiasedly validated using bootstrapping or cross-validation, before using predictions in a new data series. We discuss some of the hazards of poorly fitted and overfitted regression models and present one modelling strategy that avoids many of the problems discussed. The methods described are applicable to all regression models, but are particularly needed for binary, ordinal, and time-to-event outcomes. Methods are illustrated with a survival analysis in prostate cancer using Cox regression.
Context
In men who develop an elevated serum prostate-specific
antigen level (PSA) after having undergone a radical prostatectomy, the
natural history of progression to distant metastases and death due to
prostate cancer is unknown.
Objective
To characterize the time course of disease progression
in men with biochemical recurrence after radical prostatectomy.
Design
A retrospective review of a large surgical series with
median (SD) follow-up of 5.3 (3.7) years (range, 0.5-15 years) between
April 1982 and April 1997.
Setting An urban academic tertiary referral institution.Patients
A total of 1997 men undergoing radical
prostatectomy, by a single surgeon, for clinically localized prostate
cancer. None received neoadjuvant therapy, and none had received
adjuvant hormonal therapy prior to documented distant metastases.
Main Outcome Measures
After surgery, men were followed up with PSA
assays and digital rectal examinations every 3 months for the first
year, semiannually for the second year, and annually thereafter. A
detectable serum PSA level of at least 0.2 ng/mL was evidence of
biochemical recurrence. Distant metastases were diagnosed by
radionuclide bone scan, chest radiograph, or other body imaging, which
was performed at the time of biochemical recurrence and annually
thereafter.
Results
The actuarial metastasis-free survival for all 1997 men
was 82% (95% confidence interval, 76%-88%) at 15 years after
surgery. Of the 1997 men, 315 (15%) developed biochemical PSA level
elevation. Eleven of these underwent early hormone therapy after the
recurrence and are not included in the study. Of the remaining 304 men,
103 (34%) developed metastatic disease within the study period. The
median actuarial time to metastases was 8 years from the time of PSA
level elevation. In survival analysis, time to biochemical progression
(P<.001), Gleason score (P<.001), and PSA
doubling time (P<.001) were predictive of the probability
and time to the development of metastatic disease. An algorithm
combining these parameters was constructed to stratify men into risk
groups. Once men developed metastatic disease, the median actuarial
time to death was 5 years. The time interval from surgery to the
appearance of metastatic disease was predictive of time until death
(P<.02).
Conclusions
Several clinical parameters help predict the outcomes
of men with PSA elevation after radical prostatectomy. These data may
be useful in the design of clinical trials, the identification of men
for enrollment into experimental protocols, and counseling men
regarding the timing of administration of adjuvant
therapies.
Local failure after radical prostatectomy (RP) is common in patients with cancer extending beyond the capsule. Three prospectively randomized trials demonstrated an advantage for adjuvant radiotherapy (ART) compared with a wait-and-see (WS) policy.
To determine the efficiency of ART after a 10-yr follow-up in the ARO 96-02 study.
After RP, 388 patients with pT3 pN0 prostate cancer (PCa) were randomized to WS or three-dimensional conformal ART with 60Gy. The present analysis focuses on intent-to-treat patients who achieved an undetectable prostate-specific antigen after RP (ITT2 population)-that is, 159 WS plus 148 ART men.
The primary end point of the study was progression-free survival (PFS) (events: biochemical recurrence, clinical recurrence, or death). Outcomes were compared by log-rank test. Cox regression analysis served to identify variables influencing the course of disease.
The median follow-up was 111 mo for ART and 113 mo for WS. At 10 yr, PFS was 56% for ART and 35% for WS (p<0.0001). In pT3b and R1 patients, the rates for WS even dropped to 28% and 27%, respectively. Of all 307 ITT2 patients, 15 died from PCa, and 28 died for other or unknown reasons. Neither metastasis-free survival nor overall survival was significantly improved by ART. However, the study was underpowered for these end points. The worst late sequelae in the ART cohort were one grade 3 and three grade 2 cases of bladder toxicity and two grade 2 cases of rectum toxicity. No grade 4 events occurred.
Compared with WS, ART reduced the risk of (biochemical) progression with a hazard ratio of 0.51 in pT3 PCa. With only one grade 3 case of late toxicity, ART was safe.
Precautionary radiotherapy counteracts relapse after surgery for prostate cancer with specific risk factors.
Purpose
To investigate the prognostic utility of the Stephenson nomogram for clinically relevant endpoints, freedom from metastasis (FFM), and prostate cancer–specific survival (PCSS) in patients treated with salvage external beam radiation therapy (SRT) following a rising prostate-specific antigen (PSA) after radical prostatectomy (RP).
Methods and materials
From an institutional cohort of 575 patients treated with SRT between 1986 and 2010, the Stephenson nomogram variables were retrospectively collected and available for 179 patients. The prognostic impact of the Stephenson nomogram on 6-year freedom from biochemical failure (FFBF), FFM, and PCSS was assessed on univariate and multivariate analysis using Kaplan-Meier and Cox proportional hazards models. The prognostic utility of the Stephenson nomogram was compared with individual pretreatment, treatment, and clinical characteristics using concordance indices.
Results
In the 179 patients with all available nomogram variables, median follow-up was 85.0 months (interquartile range [IQR], 53-113) and 6-year FFBF, FFM, and PCSS were 38% (95% confidence interval [CI], 30-46), 79% (95% CI, 73-85), and 96% (95% CI, 92-100), respectively. Univariate analysis, demonstrated that the Stephenson nomogram, as a continuous variable and as a risk stratified group, was prognostic of FFBF (both, P < .0001), FFM (both, P < .0001), and PCSS (both, P ≤ .0005). When analyzing individual Stephenson nomogram variables, multivariate analysis revealed that positive surgical margins (P = .02; hazard ratio [HR], 0.4; 95% CI, 0.2-0.8) and pre-RT PSA (P = .0001; HR, 1.6; 95% CI, 1.3-2.0) were prognostic for FFM, while pre-RT PSA (P = .03; HR, 1.2; 95% CI, 1.0-1.4) was the only prognostic variable for PCSS. Concordance indices revealed the Stephenson nomogram to have superior prognostic capability for biochemical failure (0.71), distant metastasis (0.75), and prostate cancer–specific mortality (0.75) when compared with individual variables (BF all ≤ 0.65, DM all ≤ 0.67, PCSM all ≤ 0.71).
Conclusions
For patients treated with SRT for a rising PSA postprostatectomy, the Stephenson nomogram is an appropriate prognostic tool for estimating the response to treatment; however, there remains a need for improvement in current and future nomograms.
The purpose of this guideline was to provide a clinical framework for the use of radiation therapy after radical prostatectomy as adjuvant or salvage therapy.
A systematic literature review using PubMed, Embase, and Cochrane database was conducted to identify peer-reviewed publications relevant to the use of radiation therapy after prostatectomy. The review yielded 294 articles; these publications were used to create the evidence-based guideline statements. Additional guidance is provided as Clinical Principles when insufficient evidence existed.
Guideline statements are provided for patient counseling, use of radiation therapy in the adjuvant and salvage contexts, defining biochemical recurrence, and conducting a restaging evaluation.
Physicians should offer adjuvant radiation therapy to patients with adverse pathologic findings at prostatectomy (ie, seminal vesicle invastion, positive surgical margins, extraprostatic extension) and salvage radiation therapy to patients with prostate-specific antigen (PSA) or local recurrence after prostatectomy in whom there is no evidence of distant metastatic disease. The offer of radiation therapy should be made in the context of a thoughtful discussion of possible short- and long-term side effects of radiation therapy as well as the potential benefits of preventing recurrence. The decision to administer radiation therapy should be made by the patient and the multidisciplinary treatment team with full consideration of the patient's history, values, preferences, quality of life, and functional status. The American Society for Radiation Oncology and American Urological Association websites show this guideline in its entirety, including the full literature review.
Purpose:
To investigate the utility of the interval to biochemical failure (IBF) after salvage radiation therapy (SRT) after radical prostatectomy (RP) for prostate cancer as a surrogate endpoint for distant metastasis (DM), prostate cancer-specific mortality (PCSM), and overall mortality (OM).
Methods and materials:
A retrospective analysis of 575 patients treated with SRT after RP from a single institution. Of those, 250 patients experienced biochemical failure (BF), with the IBF defined as the time from commencement of SRT to BF. The IBF was evaluated by Kaplan-Meier and Cox proportional hazards models for its association with DM, PCSM, and OM.
Results:
The median follow-up time was 85 (interquartile range [IQR] 49.8-121.1) months, with a median IBF of 16.8 (IQR, 8.5-37.1) months. With a cutoff time of 18 months, as previously used, 129 (52%) of patients had IBF ≤18 months. There were no differences among any clinical or pathologic features between those with IBF ≤ and those with IBF >18 months. On log-rank analysis, IBF ≤18 months was prognostic for increased DM (P<.0001, HR 4.9, 95% CI 3.2-7.4), PCSM (P<.0001, HR 4.1, 95% CI 2.4-7.1), and OM (P<.0001, HR 2.7, 95% CI 1.7-4.1). Cox proportional hazards models with adjustment for other clinical variables demonstrated that IBF was independently prognostic for DM (P<.001, HR 4.9), PCSM (P<.0001, HR 4.0), and OM (P<.0001, HR 2.7). IBF showed minimal change in performance regardless of androgen deprivation therapy (ADT) use.
Conclusion:
After SRT, a short IBF can be used for early identification of patients who are most likely to experience progression to DM, PCSM, and OM. IBF ≤18 months may be useful in clinical practice or as an endpoint for clinical trials.
: We report the long-term results of a trial of immediate postoperative irradiation versus a wait-and-see policy in patients with prostate cancer extending beyond the prostate, to confirm whether previously reported progression-free survival was sustained.
Methods : This randomised, phase 3, controlled trial recruited patients aged 75 years or younger with untreated cT0-3 prostate cancer (WHO performance status 0 or 1) from 37 institutions across Europe. Eligible patients were randomly assigned centrally (1:1) to postoperative irradiation (60 Gy of conventional irradiation to the surgical bed for 6 weeks) or to a wait-and-see policy until biochemical progression (increase in prostate-specific antigen >0.2 mu g/L confirmed twice at least 2 weeks apart). We analysed the primary endpoint, biochemical progression-free survival, by intention to treat (two-sided test for difference at alpha=0.05, adjusted for one interim analysis) and did exploratory analyses of heterogeneity of effect. This trial is registered with ClinicalTrials.gov, number NCT00002511.
Findings : 1005 patients were randomly assigned to a wait-and-see policy (n=503) or postoperative irradiation (n=502) and were followed up for a median of 10.6 years (range 2 months to 16.6 years). Postoperative irradiation significantly improved biochemical progression-free survival compared with the wait-and-see policy (198 [39.4%] of 502 patients in postoperative irradiation group vs 311 [61.8%] of 503 patients in wait-and-see group had biochemical or clinical progression or died; HR 0.49 [95% CI 0.41-0.59]; p
Purpose:
Radical prostatectomy has decreased prostate cancer specific mortality in men with clinically localized prostate cancer. We report oncological outcomes of the longest running series of nerve sparing radical retropubic prostatectomy on the 30th anniversary of the inaugural operation.
Materials and methods:
A total of 4,478 men underwent anatomical radical retropubic prostatectomy, as performed by a single surgeon (PCW), at the Johns Hopkins Medical Institutions from 1982 to 2011, without neoadjuvant or adjuvant therapy. During a median followup of 10 years (range 1 to 29), we examined progression-free, metastasis-free and cancer specific survival.
Results:
The overall 25-year progression-free, metastasis-free and cancer specific survival rates were 68%, 84% and 86%, respectively, although there were significant differences in treatment outcomes between men treated in the pre-PSA and PSA eras. In each era, there were significant differences in progression-free, metastasis-free and cancer specific survival by D'Amico risk groups. In multivariable models considering prostatectomy features, pathological stage and grade were significantly associated with the risk of metastatic progression and disease specific mortality.
Conclusions:
Excellent prostate cancer specific survival was demonstrated up to 30 years after surgery. Clinical risk categories and pathological tumor features were significant predictors of long-term disease specific outcomes, supporting their ongoing use in risk stratification and management decisions. Anatomical radical retropubic prostatectomy continues to represent the gold standard in the surgical management of clinically localized prostate cancer to which alternate treatment options should be compared.
Multivariable regression models are powerful tools that are used frequently in studies of clinical outcomes. These models can use a mixture of categorical and continuous variables and can handle partially observed (censored) responses. However, uncritical application of modelling techniques can result in models that poorly fit the dataset at hand, or, even more likely, inaccurately predict outcomes on new subjects. One must know how to measure qualities of a model's fit in order to avoid poorly fitted or overfitted models. Measurement of predictive accuracy can be difficult for survival time data in the presence of censoring. We discuss an easily interpretable index of predictive discrimination as well as methods for assessing calibration of predicted survival probabilities. Both types of predictive accuracy should be unbiasedly validated using bootstrapping or cross-validation, before using predictions in a new data series. We discuss some of the hazards of poorly fitted and overfitted regression models and present one modelling strategy that avoids many of the problems discussed. The methods described are applicable to all regression models, but are particularly needed for binary, ordinal, and time-to-event outcomes. Methods are illustrated with a survival analysis in prostate cancer using Cox regression.
To externally validate the nomogram published by Stephenson et al. (termed the 'Stephenson nomogram') to predict disease progression after salvage radiotherapy (SRT) among patients with prostate cancer from the Shared Equal Access Regional Cancer Hospital (SEARCH) database.
We analysed data from 102 men treated with SRT for prostate-specific antigen (PSA) failure after prostatectomy, of whom 30 (29%) developed disease progression after SRT during a median follow-up of 50 months. The predicted 6-year progression-free survival (PFS) was compared to the actuarial PFS using calibration plots. The accuracy of the nomogram to risk-stratify men for progression was assessed by the concordance index.
The median PSA and PSA doubling time before SRT was 0.6 ng/mL and 10.3 months, respectively. The 6-year actuarial disease-free progression after SRT was 57% (95% confidence interval 42-69%). The overall concordance index of the Stephenson nomogram was 0.65. The nomogram predicted failure more accurately at the extremes of risk (lowest and highest) but in intermediate groups, the accuracy was less precise. Of the 11 variables used in the nomogram, only negative margins and high PSA level before SRT were significantly associated with increased disease progression.
The Stephenson nomogram is an important tool to predict disease progression after SRT following radical prostatectomy. It adequately predicted progression in SEARCH with reasonable accuracy. Also, in SEARCH, disease progression was predicted by similar disease characteristics. However, the overall modest performance of the model in our validation cohort indicates there is still room for improvement in predictive models for disease progression after SRT.
To define a prostate fossa clinical target volume (PF-CTV) for Radiation Therapy Oncology Group (RTOG) trials using postoperative radiotherapy for prostate cancer.
An RTOG-sponsored meeting was held to define an appropriate PF-CTV after radical prostatectomy. Data were presented describing radiographic failure patterns after surgery. Target volumes used in previous trials were reviewed. Using contours independently submitted by 13 radiation oncologists, a statistical imputation method derived a preliminary "consensus" PF-CTV.
Starting from the model-derived CTV, consensus was reached for a CT image-based PF-CTV. The PF-CTV should extend superiorly from the level of the caudal vas deferens remnant to >8-12 mm inferior to vesicourethral anastomosis (VUA). Below the superior border of the pubic symphysis, the anterior border extends to the posterior aspect of the pubis and posteriorly to the rectum, where it may be concave at the level of the VUA. At this level, the lateral border extends to the levator ani. Above the pubic symphysis, the anterior border should encompass the posterior 1-2 cm of the bladder wall; posteriorly, it is bounded by the mesorectal fascia. At this level, the lateral border is the sacrorectogenitopubic fascia. Seminal vesicle remnants, if present, should be included in the CTV if there is pathologic evidence of their involvement.
Consensus on postoperative PF-CTV for RT after prostatectomy was reached and is available as a CT image atlas on the RTOG website. This will allow uniformity in defining PF-CTV for clinical trials that include postprostatectomy RT.
Extraprostatic disease will be manifest in a third of men after radical prostatectomy. We present the long-term followup of a randomized clinical trial of radiotherapy to reduce the risk of subsequent metastatic disease and death.
A total of 431 men with pT3N0M0 prostate cancer were randomized to 60 to 64 Gy adjuvant radiotherapy or observation. The primary study end point was metastasis-free survival.
Of 425 eligible men 211 were randomized to observation and 214 to adjuvant radiation. Of those men under observation 70 ultimately received radiotherapy. Metastasis-free survival was significantly greater with radiotherapy (93 of 214 events on the radiotherapy arm vs 114 of 211 events on observation; HR 0.71; 95% CI 0.54, 0.94; p = 0.016). Survival improved significantly with adjuvant radiation (88 deaths of 214 on the radiotherapy arm vs 110 deaths of 211 on observation; HR 0.72; 95% CI 0.55, 0.96; p = 0.023).
Adjuvant radiotherapy after radical prostatectomy for a man with pT3N0M0 prostate cancer significantly reduces the risk of metastasis and increases survival.
This analysis was performed to define the level of serum prostate-specific antigen (PSA) measured with the Abbott IMx assay that indicates residual or progressive prostate cancer after radical retropubic prostatectomy (RRP).
Since March 1992, we have used the Abbott IMx assay to determine PSA levels. Between March 1992 and June 1994, 102 of those patients having RRPs were found to have pathologic Stage C prostate cancer. Fifty-one of these patients had at least one serum PSA measurement of 0.1 ng/mL or greater. Eight patients were excluded from the analysis because they received postoperative radiotherapy that might have influenced subsequent PSA levels. The remaining 43 patients are the subjects of this analysis and were evaluated to determine the "clinical threshold" or minimal serum PSA level after RRP indicative of progressive disease. Patients were followed for 6 to 36 months (median 23 months) from the date of the RRP. Failure was defined as a subsequent increase of PSA to greater than 0.3 ng/mL. Freedom from failure was determined using the Kaplan-Meier product limit method.
Of the patients with at least one postoperative serum PSA level of 0.1 ng/mL, the subsequent freedom from failure was 80% at 23 months as compared with 13% in patients with at least one postoperative PSA level of 0.2 ng/mL (P = 0.003).
Following RRP for pathologic Stage C prostate cancer, a solitary PSA level of 0.1 ng/mL (measured with the IMx assay) was followed by a progressive rise in PSA levels in only a minority of patients within the first 2 years after surgery. In contrast, the majority of patients with a postoperative PSA level of 0.2 ng/mL subsequently had progressively rising PSA levels. This indicates that a serum PSA level of 0.2 ng/mL is reflective of residual prostate cancer.
In men who develop an elevated serum prostate-specific antigen level (PSA) after having undergone a radical prostatectomy, the natural history of progression to distant metastases and death due to prostate cancer is unknown.
To characterize the time course of disease progression in men with biochemical recurrence after radical prostatectomy.
A retrospective review of a large surgical series with median (SD) follow-up of 5.3 (3.7) years (range, 0.5-15 years) between April 1982 and April 1997.
An urban academic tertiary referral institution.
A total of 1997 men undergoing radical prostatectomy, by a single surgeon, for clinically localized prostate cancer. None received neoadjuvant therapy, and none had received adjuvant hormonal therapy prior to documented distant metastases.
After surgery, men were followed up with PSA assays and digital rectal examinations every 3 months for the first year, semiannually for the second year, and annually thereafter. A detectable serum PSA level of at least 0.2 ng/mL was evidence of biochemical recurrence. Distant metastases were diagnosed by radionuclide bone scan, chest radiograph, or other body imaging, which was performed at the time of biochemical recurrence and annually thereafter.
The actuarial metastasis-free survival for all 1997 men was 82% (95% confidence interval, 76%-88%) at 15 years after surgery. Of the 1997 men, 315 (15%) developed biochemical PSA level elevation. Eleven of these underwent early hormone therapy after the recurrence and are not included in the study. Of the remaining 304 men, 103 (34%) developed metastatic disease within the study period. The median actuarial time to metastases was 8 years from the time of PSA level elevation. In survival analysis, time to biochemical progression (P<.001), Gleason score (P<.001), and PSA doubling time (P<.001) were predictive of the probability and time to the development of metastatic disease. An algorithm combining these parameters was constructed to stratify men into risk groups. Once men developed metastatic disease, the median actuarial time to death was 5 years. The time interval from surgery to the appearance of metastatic disease was predictive of time until death (P<.02).
Several clinical parameters help predict the outcomes of men with PSA elevation after radical prostatectomy. These data may be useful in the design of clinical trials, the identification of men for enrollment into experimental protocols, and counseling men regarding the timing of administration of adjuvant therapies.
The most appropriate definition of biochemical progression after radical prostatectomy and radiation therapy is uncertain. We analyzed the effect of using various prostate specific antigen (PSA) end point definitions for defining biochemical progression after radical prostatectomy and attempted to determine the best PSA cut point to use. Aspects of the American Society for Therapeutic Radiology and Oncology (ASTRO) definition of biochemical failure after radiation therapy are also analyzed in our radical prostatectomy cases.
A total of 2,782 men with clinically localized prostate cancer (cT1-T2) who had undergone radical prostatectomy between 1987 and 1993 were reviewed. All patients had regular PSA determinations from surgery through followup. Analysis was limited to patients who did not receive adjuvant treatment within 90 days of radical prostatectomy. Biochemical, PSA progression-free percent after radical prostatectomy was determined by the Kaplan-Meier method using several PSA cut points, including 0.2, 0.3, 0.4 and 0.5 ng./ml. or greater, as well as 0.4 ng./ml. or greater and increasing. Progression-free percent was also assessed using the ASTRO definition, which is 3 increases in PSA. To determine which PSA level was most appropriate to define progression after radical prostatectomy, the percentage of patients with a continued PSA increase after reaching each cut point was determined. The relationship between the maximum PSA within 3 years of surgery and subsequent development of clinical disease was also assessed.
Progression-free percent was dependent on the PSA cut point used. Biochemical progression-free percentages for cut points 0.2, 0.3, 0.4 and 0.5 ng./ml. or greater were 62%, 72%, 76% and 78% at 5 years, and 43%, 54%, 59% and 61% at 10 years, respectively. A subsequent increase in PSA was noted in 49%, 62% and 72% of patients who had PSA 0.2, 0.3 and 0.4 ng./ml., respectively. Subsequent clinical progression (local or systemic) was directly related to the maximum PSA attained within 3 years of radical prostatectomy (p=0.0001). Progression-free percent for definitions requiring multiple increases in PSA were dependent on when the event was said to occur. Backdating of events at or before the first PSA (ASTRO definition) resulted in poorer, short-term progression-free percent (78% at 5 years), with little apparent likelihood of long-term failure (78% at 10 years). Coding the event at the last PSA increase when all event criteria had been met resulted in more realistic progression-free percent estimates (85% at 5 and 59% at 10 years).
Biochemical, PSA progression rates vary markedly depending on the method used to define PSA failure. Methods that require multiple increasing PSA values, for example the ASTRO definition, give misleading results, especially if the event time is backdated. Standards for defining PSA progression would allow more consistent and comparable progression estimates after radical prostatectomy. PSA 0.4 ng./ml. or greater may be the most appropriate cut point to use since a significant number of patients with lower PSA do not have a continued increase in it.
We retrospectively reviewed the clinical followup for a large series of men with clinically localized prostate cancer who underwent radical retropubic prostatectomy to identify clinical and/or pathological indicators of biochemical (prostate specific antigen [PSA]) recurrence. We then used those indicators to develop multivariate models for determination of recurrence probability following radical retropubic prostatectomy.
From 1982 to 1999, 2,091 consecutive men underwent radical retropubic prostatectomy and pelvic lymphadenectomy for clinically localized adenocarcinoma of the prostate (clinical stage T1c or T2 disease with Gleason score 5 or greater). Actuarial analysis was performed comparing freedom from biochemical recurrence after radical retropubic prostatectomy (PSA 0.2 ng./ml. or greater.) using the Kaplan-Meier method. Event time distributions for the time to recurrence were compared using the log rank statistic or the Cox proportional hazards regression model. The first model was developed using preoperative variables only and the second model using all available variables. Observed and predicted recurrence-free survival curves for different models were compared to select a model for calculation of predicted recurrence-free probabilities and confidence intervals.
With a median followup of 5.9 years (range 1 to 17) 360 men (17%) had biochemical recurrence. Overall actuarial 5, 10 and 15-year biochemical recurrence-free survival rates were 84%, 72% and 61%, respectively. The relative risk of biochemical recurrence following surgery decreased with time, even after adjusted for other perioperative parameters. Variables identified for the preoperative model were biopsy Gleason score, clinical TNM stage and PSA. Variables identified for the postoperative model were prostatectomy Gleason score, PSA and pathological organ confinement status. Nomograms were generated and corrected for the decreasing relative risk of biochemical recurrence over time.
Using 3 preoperative or postoperative parameters, these nomograms can easily be used to determine the 3, 5, 7 and 10-year biochemical recurrence-free survival probabilities among men who undergo radical retropubic prostatectomy for clinically localized prostate cancer in the modern era.
We updated a long-term cancer control outcome in a large anatomical radical retropubic prostatectomy (RRP) series. We also evaluated the perioperative parameters that predict cancer specific outcomes following surgery.
From May 1983 to February 2003, 1 surgeon (WJC) performed RRP in 3,478 consecutive men. Patients were followed with semiannual serum prostate specific antigen (PSA) tests and annual digital rectal examinations. We used Kaplan-Meier product limit estimates to calculate actuarial 10-year probabilities of biochemical progression-free survival, cancer specific survival and overall survival. Multivariate Cox proportional hazards models were used to determine independent perioperative predictors of cancer progression.
At a mean followup of 65 months (range 0 to 233) actuarial 10-year biochemical progression-free, cancer specific and overall survival probabilities were 68%, 97% and 83%, respectively. On multivariate analysis biochemical progression-free survival probability was significantly associated with preoperative PSA, clinical tumor stage, Gleason sum, pathological stage and treatment era. Cancer specific survival and overall survival rates were also significantly associated with clinicopathological parameters.
RRP can be performed with excellent survival outcomes. Favorable clinicopathological parameters and treatment in the PSA era are associated with improved cancer control.
This study was performed to evaluate the results and prognostic factors associated with radiotherapy for a detectable serum prostate specific antigen level after radical prostatectomy.
From July 1987 through July 2003, 368 patients received radiotherapy for a detectable prostate specific antigen level (biochemical relapse) as the sole evidence of recurrence after radical prostatectomy for node negative prostate cancer. Estimated survival and relapse-free probabilities were obtained via Kaplan-Meier estimation. Associations of patient factors with survival and biochemical relapse were investigated using Cox proportional hazards models.
With a median followup of 5 years the 5 and 8-year freedom from biochemical relapse were an estimated 46% (95% CI 41%-53%) and 35% (95% CI 29%-43%) while survival was 92% (95% CI 89%-95%) and 80% (95% CI 74%-87%), respectively. Patient and treatment variables showing evidence of association with biochemical relapse on multivariate analysis included pathological stage T3a or less vs T3b (seminal vesicle involvement, p = 0.029), pathological Gleason score 7 or less vs 8 or greater (p <0.001) and pre-radiotherapy prostate specific antigen (p <0.001). Four biochemical failure risk groups were created by assigning seminal vesicle involvement, Gleason score and pre-radiotherapy prostate specific antigen each a score of 0 to 2. These individual scores were summed. The freedom from biochemical failure at 5 years for each risk group was 0 to 1-69%, 2-53%, 3-26% and 4 to 5-6%.
The presence of seminal vesicle involvement and high Gleason score in the radical prostatectomy specimen are inherent predictors of adverse outcome. Early referral for salvage radiotherapy can decrease subsequent biochemical relapse.
The American Urological Association Prostate Guideline Update Panel was charged with updating the Guidelines for Clinically Localized Prostate Cancer. In assessing outcomes with treatment, it became apparent that a highly variable number of definitions exist with respect to biochemical recurrence. Herein, we review the variability in published definitions of biochemical recurrence and make recommendations directed toward improving this terminology by recommending a standard definition in patients treated with radical prostatectomy.
Four PubMed literature searches were performed between May 2001 and April, 2004 and covered articles published from 1991 through early 2004. The search terms included the MeSH major headings of prostate cancer and prostatic neoplasm. All potentially relevant articles were retrieved and a more detailed screen for relevance was performed. An article was considered relevant if it reported treatment outcomes of patients with clinical T1 or T2N0M0 prostate cancer. Data extractors recorded the definition of biochemical recurrence and definitions were then collapsed into categories representing the same criteria. The results of biochemical failure were subcategorized by initial treatment.
Of 13,800 citations, a total of 436 articles were selected. Among these, a total of 145 articles contained 53 different definitions of biochemical recurrence for those treated with radical prostatectomy. Of these, the most common definition (35) was a prostate specific antigen of >0.2 ng/mL or a slight variation thereof. In addition, a total of 208 articles reported 99 different definitions of biochemical failure among those treated with radiation therapy. Of these, the American Society for Therapeutic Radiology and Oncology definition (70) and/or a variation thereof was the most commonly reported. In total, 166 different definitions of biochemical failure were identified. Following radical prostatectomy, the Panel recommends defining biochemical recurrence as an initial serum prostate specific antigen of > or =0.2 ng/mL, with a second confirmatory level of prostate specific antigen of >0.2 ng/mL. The Panel recommends the use of the American Society for Therapeutic Radiology and Oncology criteria for patients treated with radiation therapy and acknowledges that these criteria will soon be updated although not yet published.
A high degree of variability in the definition of biochemical recurrence exists following treatment for localized prostate cancer. Strict definitions for biochemical recurrence are necessary to identify men at risk for disease progression and to allow meaningful comparisons among patients treated similarly. The Panel acknowledges the American Society for Therapeutic Radiology and Oncology criteria and future modifications thereof for those receiving radiation therapy and recommends the newly developed American Urological Association criteria for those treated with radical prostatectomy. The purpose for the establishment of this standard is for data reporting purposes and for comparison of similarly treated patients. It is not intended to represent a threshold value for which to initiate treatment. The Panel acknowledges that the clinical decision to initiate treatment will be dependent on multiple factors including patient and physician interaction rather than a specific prostate specific antigen threshold value.
Southwest Oncology Group (SWOG) trial 8794 demonstrated that adjuvant radiation reduces the risk of biochemical (prostate-specific antigen [PSA]) treatment failure by 50% over radical prostatectomy alone. In this analysis, we stratified patients as to their preradiation PSA levels and correlated it with outcomes such as PSA treatment failure, local recurrence, and distant failure, to serve as guidelines for future research.
Four hundred thirty-one subjects with pathologically advanced prostate cancer (extraprostatic extension, positive surgical margins, or seminal vesicle invasion) were randomly assigned to adjuvant radiotherapy or observation.
Three hundred seventy-four eligible patients had immediate postprostatectomy and follow-up PSA data. Median follow-up was 10.2 years. For patients with a postsurgical PSA of 0.2 ng/mL, radiation was associated with reductions in the 10-year risk of biochemical treatment failure (72% to 42%), local failures (20% to 7%), and distant failures (12% to 4%). For patients with a postsurgical PSA between higher than 0.2 and <or = 1.0 ng/mL, reductions in the 10-year risk of biochemical failure (80% to 73%), local failures (25% to 9%), and distant failures (16% to 12%) were realized. In patients with postsurgical PSA higher than 1.0, the respective findings were 94% versus 100%, 28% versus 9%, and 44% versus 18%.
The pattern of treatment failure in high-risk patients is predominantly local with a surprisingly low incidence of metastatic failure. Adjuvant radiation to the prostate bed reduces the risk of metastatic disease and biochemical failure at all postsurgical PSA levels. Further improvement in reducing local treatment failure is likely to have the greatest impact on outcome in high-risk patients after prostatectomy.
The GPSM (Gleason, prostate specific antigen, seminal vesicle and margin status) scoring algorithm is a user friendly model for predicting biochemical recurrence following radical retropubic prostatectomy. It was developed from patients who underwent radical retropubic prostatectomy from 1990 to 1993. We investigated the predictive ability of GPSM in the contemporary era.
We identified 2,728 patients who underwent radical retropubic prostatectomy for prostate cancer from 1997 to 2000 at our institution. Cox proportional hazard regression models were used to develop multivariate scoring algorithms. Harrell's measure of concordance was used to compare the competing models.
In the contemporary era each GPSM feature remained significantly associated with biochemical recurrence in a multivariate model (each p <0.001). Harrell's measure of concordance for the algorithm was 0.706 vs 0.718 in the original study. After adjusting for GPSM on multivariate analysis Gleason primary 4/5 (p <0.001), DNA ploidy (p = 0.018) and tumor size (p <0.001) were associated with biochemical recurrence. However, none of these features increased Harrell's measure of concordance greater than 0.01 when added to the GPSM model. In addition, using the original 1990 to 1993 cohort, 495 patients with a GPSM score of 10 or greater were significantly more likely to die of prostate cancer compared with 2,169 with a GPSM score of less than 10 (at 15 years 13% vs 2%, HR 6.5, p <0.001).
The GPSM scoring algorithm is a simple predictive model that remains associated with biochemical recurrence in the contemporary era. In addition, to our knowledge the GPSM algorithm is the first nomogram associated with survival in patients with prostate cancer.
The randomized controlled European Organisation for Research and Treatment of Cancer (EORTC) trial 22911 studied the effect of radiotherapy after prostatectomy in patients with adverse risk factors. Review pathology data of specimens from participants in this trial were analyzed to identify which factors predict increased benefit from adjuvant radiotherapy.
After prostatectomy, 1,005 patients with stage pT3 and/or positive surgical margins were randomly assigned to a wait-and-see (n = 503) and an adjuvant radiotherapy (60 Gy conventional irradiation) arm (n = 502). Pathologic review data were available for 552 patients from 11 participating centers. The interaction between the review pathology characteristics and treatment benefit was assessed by log-rank test for heterogeneity (P < .05).
Margin status assessed by review pathology was the strongest predictor of prolonged biochemical disease-free survival with immediate postoperative radiotherapy (heterogeneity, P < .01): by year 5, immediate postoperative irradiation could prevent 291 events/1,000 patients with positive margins versus 88 events/1,000 patients with negative margins. The hazard ratio for immediate irradiation was 0.38 (95% CI, 0.26 to 0.54) and 0.88 (95% CI, 0.53 to 1.46) in the groups with positive and negative margins, respectively. We could not identify a significant impact of the positive margin localization.
Provided careful pathology of the prostatectomy is performed, our results suggest that immediate postoperative radiotherapy might not be recommended for prostate cancer patients with negative surgical margins. These findings require validation on an independent data set.
Prostate specific antigen is a glycoprotein found almost exclusively in normal and neoplastic prostate cells. Prostate specific antigen doubling time, or the change in prostate specific antigen over time, has emerged as a useful predictive marker for assessing disease outcome in patients with prostate cancer. It is important to agree on definitions and values for the calculation of prostate specific antigen doubling time, and to develop a common approach to outcome analysis and reporting.
In September 2006 a conference was held at the National Cancer Institute in Bethesda, Maryland to define these parameters and develop guidelines for their use.
The Prostate Specific Antigen Working Group defined criteria regarding prostate specific antigen doubling time including the calculation of prostate specific antigen doubling time, evidence to support prostate specific antigen doubling time as a predictive factor in the setting of biochemical recurrence and the use of prostate specific antigen doubling time as a stratification factor in clinical trials.
We propose that investigators calculate prostate specific antigen doubling time before enrolling patients in clinical studies and calculate it as an additional measurement of therapeutic activity. We believe we have developed practical guidelines for the calculation of prostate specific antigen doubling time and its use as a measurement of prognosis and outcome. Furthermore, the use of common standards for prostate specific antigen doubling time in clinical trials is important as we determine which treatments should progress to randomized trials in which "hard" end points such as survival will be used.
A prostate-specific antigen doubling time of <6 months is prognostic for metastasis and prostate cancer-specific death for patients receiving salvage radiation therapy post radical prostatectomy
- Jackson
Jackson WC, Johnson SB, Li D et al. A prostate-specific antigen doubling
time of <6 months is prognostic for metastasis and prostate cancerspecific death for patients receiving salvage radiation therapy post radical
prostatectomy. Radiat Oncol 2013; 8: 170
- Harrell FE Jr
- Lee KL
- Mark DB
Adjuvant and salvage radiation therapy after prostatectomy: American Society for Radiation Oncology/American Urological Association guidelines
- Rk Valicenti
- I Thompson
- Jr
- P Albertsen
Valicenti RK, Thompson I Jr, Albertsen P et al. Adjuvant and salvage
radiation therapy after prostatectomy: American Society for Radiation
Oncology/American Urological Association guidelines. Int J Radiat Oncol
Biol Phys 2013; 86: 822-8
Department of Radiation Oncology
- Katherine S Correspondence
- Tzou
Correspondence: Katherine S. Tzou, Department of Radiation
Oncology, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL
32224, USA.
USA. e-mail: Tzou.Katherine@mayo.edu Abbreviations: AST, androgen-suppression therapy; ASTRO, American Society for Radiation Oncology; BCR, biochemical recurrence; EORTC, European Organisation for the Research and Treatment of Cancer
- Katherine S Correspondence
- Tzou
Correspondence: Katherine S. Tzou, Department of Radiation
Oncology, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL
32224, USA.
e-mail: Tzou.Katherine@mayo.edu
Abbreviations: AST, androgen-suppression therapy; ASTRO,
American Society for Radiation Oncology; BCR, biochemical
recurrence; EORTC, European Organisation for the Research
and Treatment of Cancer; RP, radical prostatectomy; RR,
relative risk; (S)RT, salvage radiation therapy; SWOG,
Southwest Oncology Group.