OBJECTIVES: To analyze biochemical recurrence criteria, attending to different PSA-cut-points referred in the literature, and to review prostate cancer natural history. METHODS: Review of the literature through a Medline search. CONCLUSIONS: A PSA of 0.4 ng/ml followed by a value higher than the ﬁrst, are the values that better deﬁne metastatic progression, while a PSA of 0.2 ng/ml followed by a value higher than the ﬁrst could be more appropriate to deﬁne patients about to receive salvage radiotherapy. Nevertheless we need new markers in order to improve prognostic and natural history knowledge.
Prostate speciﬁc antigen (PSA) is the main tool in the follow-up of prostate cancer patients after deﬁnitive therapy. It´s widely used as an early marker to value treatment success. Biochemical recurrence predicts metastatic disease progression and prostate cancer- speciﬁc mortality. In 1996, the American Society for Therapeutic Radiology and Oncology (ASTRO) provided a deﬁnition of biochemical failure after radiotherapy, based on three consecutive increases in PSA after nadir. As more experience was gained using the proposed deﬁnition and follow up duration in the PSA era matured, deﬁciencies and controversial issues emerged, so more recently proposed candidate deﬁnitions have provided consistent outcome. In view of the criticisms, a second consensus conference was held on 2005, with “nadir + 2 ng/ml” accepted as standard deﬁnition.The natural history and evidence of PSA kinetic parameters and different deﬁnitions of biochemical failure after external beam radiation therapy and/or brachytherapy are reviewed in the following article.
Radiotherapy is a curative treatment for localized prostate cancer in its modalities of brachytherapy (BT) and external beam radiotherapy (EBRT). A temporary increase in prostate- speciﬁc antigen (PSA) values following a radiotherapy treatment coupled with a decrease without therapeutic intervention may happen in 30% of the patients. This phenomenon is known as PSA bounce and lacks prognostic effect in relation to tumor control. Additionally, it produces anxiety in the patient because of the fear of failure, and in the physicists due to the uncertainty about the state of the tumor. The etiology and pathogenesis are still unknown. Several factors associated with the tumor and the treatments have been evaluated in the studies which analyze this phenomenon, the age is the only observed factor with the highest consistency as a bounce predictor. The deﬁnition of biologic failure (BF) after EBRT or BT with or without androgenic deprivation (ADT) according to Phoenix criteria, which considers an increase of at least 2 ng/ml over PSA nadir, enables better taking the bounce phenomenon into account, although is not free from false BF that may affect to the relapse-free survival in patients with follow-up shorter than 3 years.
In this narrative review we present the concept of nomogram in the context of predictive models in prostate cancer. In fact we try to answer the following questions from a practical and critical point of view: What is a nomogram? How to read and evaluate nomograms? What nomograms predict biochemical relapse in prostate cancer after lo-cal treatment, either surgery or radiotherapy? Why are nomogra-ms better than risk groups stratiﬁcation? And, ﬁnally, Why don`t clinicians use nomograms in fact?
The recent development in the imaging diagnostic techniques have improved the diagnosis of prostate cancer recurrence, mainly if it is local. Nowadays, the use of MRI based morphologic and functional techniques has a better sensitivity for the diagnosis of local recurrence. Integration of MR imaging data with ultrasound guided transrectal biopsies has improved the accuracy in the diagnosis of local recurrence of the disease. However, there is a need for new or better methods that enable the detection of secondary systemic disease, the conventional methods be-ing (CT and bone scintigraphy) insufﬁciently sensitive. Nowadays the PET-CT is the most promising technique, for which the use of new radio- pharmaceuticals (on experimental phases) would allow the diagnosis of systemic disease more accurately. The combined and complimentary use of the different imaging techniques available, will permit to diagnose relapsing disease earlier and better, setting the ﬁeld up for more adequate treatments, reducing morbility and giving the opportunity to offer local, less aggressive treatments.
Clinical nomograms based on Gleason grade, tumor stage, and serum PSA are still the best predictors of prostate cancer (PC) outcome. The biotechnological advancements achieved in the last decade represent a remarkable source for new prognostic and predictive tissue and serum molecular biomarkers. In this review, we will summarize conventional PC prog- nostic biomarkers and focus on novel identiﬁed biomarkers for PC early diagnosis and progression that might be used in the future. Although they are not ready for widespread, routine use, there are reasons to believe that future models will combine these markers with traditional pre-treatment and treatment-related variables and will improve our ability to predict outcome and select the optimal treatment.
OBJECTIVE: Review of the Guidelines which have major impact on the urological ﬁeld, in order to compare and to know their recommendations in the diagnosis and management of biochemical relapse after a healing treatment of prostate cancer (radical prostatectomy or radiotherapy). METHODS: We review the Guidelines of the European Urological Association (EAU), the American Urological Association (AUA), of the National Comprehensive Cancer Network (NCCN) and those of the National Institute for Health and Clinical Excellence (NICE), as well as the scientiﬁc evidence on which they are based. RESULTS: In this paper we state the complexity of the subject being dealt with and coincidences and differences among them. The deﬁnition of relapse varies depending on whether the patient has undergone either radical prostatectomy or radiotherapy. Regarding treatment, in the ﬁrst case early radiotherapy is the treatment of choice, but recommendations after radiotherapy are not so speciﬁc. CONCLUSION: Clinical Guidelines represent a great aid in decision making for the professional. Guidelines give recommendations with a higher o lower degree of scientiﬁc evidence and must be evaluated regularly to include new evidences which are coming through.
Radical prostatectomy is an excellent salvage method for patients with prostatic cancer when radical radiotherapy or brachytherapy fail. To deﬁne local failure is not always reliable; nevertheless, performing a prostatic biopsy two years after treatment could reach an early diagnosis. Another accepted attitude is to perform the biopsy after biochemical recurrence, but sometimes the pathological stage is already locally advanced tumor. It is also difﬁcult to determine which patients are suitable for this rescue treatment, probably those with locally conﬁned tumors and with favorable PSA kinetics, PSA velocity below 2.0 or a PSA doubling time over 12 months, and in whom detectable PSA is reached 2 years after treatment. These patients are suitable for radical prostatectomy if they have a live expectancy of more than 10 years. Although rescue radical prostatectomy has a higher rate of complications and worse functional results, cancer-speciﬁc survival rates are high, and remain high after 15 years of follow-up. Currently, new surgical improvements and new radiotherapy technology are diminishing surgical complications and improving functional results. In summary radical prostatectomy is a feasible rescue procedure after radiotherapy failure although the complications rate remains higher than prostatectomy as initial therapy.
Radical Radiotherapy constitutes a useful therapeutic option for localized prostate cancer. Almost one third of prostate cancer patients choose this alternative to treat the disease. Despite modiﬁcations in the technique as intensity modulation, 3D conformational radiotherapy or computer-assisted brachytherapy, a signiﬁcant percentage of these patients will show an increase in PSA values after radiation. Local relapse without distant disease and PSA less than 10 ng/ml are candidates for salvage therapy. Cryotherapy has already become a curative treatment option in this group of patients. Recent technological as well as surgical advances in salvage-cryotherapy have reduced dramatically complications and progressively increase the interest on this alternative.
OBJECTIVES: To evaluate the efﬁcacy and safety of High Intensity Focused Ultrasound (HIFU) as salvage treatment after radical radiotherapy in prostate cancer (PC). METHODS: We reviewed the literature through databases and published articles that refer to this treatment between 2000 and 2010. We evaluated oncological results and adverse effects, compared with those published in conjunction with other therapies. RESULTS: We evaluated the different series, which include the results of the two devices currently available, all with their initial results and those that are in the process of dose adjustment.Generally, it can be said that the biggest problem of all is that initial morbidity is reduced as the surgeon gains experience with the treatment. We must stress the importance of the short series that are evaluated, especially in follow-up time and number of patients. Also, except for a recently published systematic review, no prospective studies are published. The results from different series are compared with existing literature regarding to other PC treatments. CONCLUSIONS: In spite of published results, the treatment with HIFU for prostate cancer recurrence after radiotherapy is an option that should be considered. Especially considering that, it is important to delay the development of the disease in these patients, and there are no other alternatives that have proven to be effective. Further research is needed to explore the use of HIFU in the treatment of PC. Anyway, it is essential to publish comparative prospective series and series with more patients and longer follow-up to draw deﬁnitive conclusions.
To date, the role of hormonal therapy (HT) after biochemical failure, when to initiate it, the therapeutic scheme and duration remains controversial due to the absence of well designed randomized trials analyzing the overall survival of patients. In clinical practice, the most widely spread treatment in this scenario is hormonal therapy with LH-RH ana- logues. However, the scientiﬁc support for this issue is very weak. We are extrapolating the beneﬁts proven for early vs delayed HT in advanced prostate cancer, to asymptomatic patients presenting just an increase in PSA. These patients usually have a long time disease- history until development of metastasis. It should also be noticed the harmful secondary effects acquired with the time of employment of hormotherapy. Probably patients suffering a Gleason score > 8 and PSA doubling time <12 months could obtain a beneﬁt from an early castration treatment, even more if they are young (grade 2c). Except in selected cases of local treat- ment as radiotherapy, the decision for early or delayed hormonal therapy should be taken carefully with patient consensus. The alternatives for hormonal treatment to preserve sexual function, as intermittent treatment, antiandrogen monotherapy, or antiandrogen plus 5 alpha reductase inhibitors, are very attractive in this scenario. However due to the short time experience with these modalities of treatment should be evaluated with caution.
Adjuvant radiotherapy (RT) has proven to be more effective in patients at high risk of relapse than salvage RT when this relapse occurs. To optimize its use we must identify the subset of patients at greater risk of residual microscopic disease after surgery, since in them the likelihood of 5-10 year biochemical failure can reach 60%. There are many studies on the subject in which these factors are identiﬁed, which in general are: presence of positive margins and capsular or seminal vesicle involvement (T3a-b). Of these, it seems that the presence of positive margins is the most powerful predictor of relapse. With regard to radiotherapy, there is variability in the dose to give and volume treated. In general, the dose in most series is ≥ 60 Gy, reaching some authors up to 70 Gy. As to the association or not hormone therapy (HT) and adjuvant radiotherapy, it is a subject of debate and so far no results of studies demonstrate a sufﬁcient beneﬁt, so it should be individualized, weighing potential beneﬁts in high risk patients against side effects.
We review salvage external beam radiotherapy for biochemical recurrence after radical prostatectomy. Having deﬁned recurrence, we analyze the risk factors of local recurrence and systemic evaluation of patients scheduled to undergo salvage radiotherapy. New techniques in external radiation, doses and volumes help us to deﬁne the areas minimizing treatment toxicity and improving the quality of the patient. We analyzed the literature to improve the therapeutic approach, based on currently known data, pending completion of further clinical trials. We describe a review about radiotherapy in biochemical failure after radical prostatectomy.
The best treatment option for patients with prostate cancer who experience local relapse after external beam radiation therapy remains uncertain. Salvage brachytherapy, cryotherapy, HIFU and radical prostatectomy have shown varying biochemical and quality-of-life outcomes according to disease-related and patient-related factors, but follow-up data are still short. It seems clear that careful patient selection for salvage brachytherapy is essential for good clinical and quality- of-life outcomes. We present a review of the currently available experiences of brachytherapy as salvage treatment after failure to external beam radiotherapy.
To evaluate the pathological variables predictive of biochemical recurrence after radical prostatectomy and their implications for decision making in the adjuvant setting. METHODS: 684 patients with localized prostate cancer who were treated with radical prostatectomy between 1996 and 2007. Before surgery they were classified according to D’Amico risk groups for recurrence. Following prostatectomy the following variables were collected: Gleason score, pathological stage, capsular invasion, surgical margins, perineural invasion and percentage of involvement in the piece. Univariate analysis was performed and subsequently adjusted using a Cox proportional hazards model (method enter).RESULTS: The median follow up of the series was 61 months. 29.1% of patients had biochemical recurrence. Overall mortality of the series was 4.9% and cancerspecific mortality 1.2%. In univariate analysis the Gleason score of surgical specimens, capsular invasion, perineural invasion, involvement of surgical margins, pathological stage and percentage of involvement of the piece had statistically significant (p < 0.001) relation with biochemical recurrence. In multivariate analysis, a Gleason score ≥ 8 in the surgical specimen (HR = 3.08), existence of affected surgical margins (HR = 2.98), pT3 stage (HR = 1.61) and involvement of more than 50% of the piece by cancer (HR = 3.39) were identified as independent predictors of biochemical recurrence. Stratifying by independent predictors of biochemical recurrence (pT, Gleason score and margin), patients with at least 2 of these factors had an incidence of biochemical recurrence at 5 years exceeding 50%.CONCLUSIONS: Patients who have a Gleason score ≥ 8, positive margins, pT3 tumour or a percentage of >50% after prostatectomy have an increased risk of biochemical recurrence. Patients with at least 2 predictors of relapse have a probability of recurrence over 50% in the first 5 years of recurrence and should therefore be candidates for adjuvant radiotherapy
OBJECTIVES: The aim of this study is to analyze the outcomes obtained after External-Beam Radiotherapy (3D EBRT) in patients with prostate cancer. METHODS: The study includes 503 patients (p) treated at the Hospital General Universitario Gregorio Marañón in Madrid, diagnosed between 2000-2007, with low, intermediate or high risk prostate cancer (D’Amico risk groups), treated with 3D EBRT. Biochemical recurrence (BR) was deﬁned as nadir +2 following Phoenix’s criterion. The median follow-up was 59 months (range 3.4-104.2). RESULTS: Biochemical relapse-free survival (bRFS) rates at 5 and 8 years were 88±2% and 76±3%, respectively. Multivariate analysis indicated initial PSA (p <0.02), perineural invasion in biopsy specimen (p <0.00), EBRT dose (p = 0.01) and the use of androgen deprivation therapy (ADT) (p = 0.00) to be independent predictors of relapse. Nadir PSA value <0.3 ng/ml was associated with the best 5-year bRFS (96.6% versus 56.5% if nadir PSA > 1.3 ng/ml).Late urinary and rectal toxicity ≥ 3 was lower than 5%. Active rescue treatment was indicated in 85% of patients. Only 10 patients died of prostate cancer. CONCLUSION: The biochemical failure rate is determined by classical pre-treatment features (initial PSA level, risk group, perineural invasion) and low- dose EBRT (≤ 72 Gy), nadir PSA value and the use of ADT in intermediate and high risk groups.
OBJECTIVES: To compare the biochemical relapse-free survival between radical prostatectomy and radiotherapy in patients with localized prostate cancer of low and intermediate recurrence risk. METHODS: A retrospective study of 435 patients with localized prostate cancer, radical prostatectomy was performed in 65% of patients and radiotherapy was completed in 35%. The Kaplan-Meier Estimator was used to assess the biochemical relapse-free survival and long-rank test, Breslow and Tarone-Ware to evaluate the differences between the groups with conﬁdence intervals at 95%. RESULTS: The median follow-up of the series was 60 months (3-106). Biochemical recurrence was diagnosed in 21% of patients: 22% of those were treated with prostatectomy and 19% with radiotherapy (p = 0.47). No signiﬁcant differences were observed according to risk group (p = 0.60 in the low risk and p = 0.32 in the intermediate risk). Tree, ﬁve and seven-year actuarial biochemical recurrence-free survival for prostatectomy were 84%, 75% and 70%, while for radiotherapy were 97%, 84% and 64% respectively. CONCLUSIONS: There are no signiﬁcant differences in actuarial biochemical recurrence free survival in patients with localized prostate cancer of low and intermediate risk treated with prostatectomy or radiation therapy. Due to the crossing of the survival curves we do not rule out that with longer follow-up these results could be modiﬁed.
Castration resistant prostatic carcinoma (CRPC) is deﬁned as tumor progression despite an effective castration (serum testosterone levels< 50ng/dL). Biochemical progression requires at least two successive increases from the previous lowest value of serum prostate-speciﬁc antigen (PSA) spaced at least a week, and with a minimum value of 2 ng/mL. In patients receiving complete androgen blockade, antiandrogen should be discontinued prior to diagnosis of CRPC. CPRC is a heterogeneous entity. Baseline PSA and PSA velocity seem to be the most important prognostic factors in patients with biochemical relapse as the only manifestation of CRPC. Some of these patients can be followed without treatment until disease progression. Because of a large proportion of tumors progressing under androgen deprivation therapy remain hormone- dependent, the use of other hormonal therapies has been the preferred treatment for the majority of these patients. Besides inhibitors of adrenal steroidogenesis, other novel hormonal approaches are currently under investigation to avoid the effect of the activated androgenic receptor on the tumor cell. In recent years there has been an important development of immunotherapy, which has demonstrated to increase survival in CRPC oligosymptomatic patients. First and second line chemotherapy in CRPC are associated with an increase in overall survival, but they are usually recommended for patients with metastases. Until the results of ongoing trials are available, the type and timing of the treatment for patients with CRPC and biochemical recurrence should be individualized.
Routine monitoring of PSA in patients with localized prostate cancer radically treated permits to identify those with biochemical recurrence only. Treatment options for biochemical failure include observation, surgery, radiotherapy alone or combined with hormonal therapy, brachytherapy, cryotherapy and hormone therapy exclusively. These treatments determine a speciﬁc pattern of changes (urinary function, bowel, sexual and hormonal) that can negatively impact the quality of life, so that the indication must be made in a judicious way and always in consonance with patient’s expectations and preferences. Decisions on how and when to treat biochemical failure are complicated and the impact of salvage therapy on clinical outcome is unknown. Rates of prostate cancer control after salvage therapy with prostatectomy, brachytherapy or cryotherapy vary between 20-80% of cases according to selected patient characteristics. Because individuals with BF may be clinically asymptomatic for many years without treatment, it is essential that physicians and patients have a clear understanding of the potential impact of these on the quality of life.