Favorable-risk Prostate Cancer Research Articles

WHEN ‘DUELING TECHNOLOGIES’ ARE MISTAKEN FOR PROGRESS

Prostate cancer is increasingly being diagnosed at an early stage. Because these tumors are organ-confined, they have a favorable prognosis and an expected long survival, often without therapy. Despite data (1) suggesting overtreatment of newly diagnosed patients, the majority of patients will receive definitive treatment, with only 8.2% electing deferred treatment, according to a recent US survey.(2) The need to produce a safe, effective, and easily applied method to treat these cancers has prompted both academia and industry to respond with new technologies in a duel to claim progress in treatment. It is no surprise then that a proliferation of refinements in surgery and radiation and new technologies to deliver alternative energy sources have been applied to control favorable-risk prostate cancer. However, many of these approaches are applied clinically with little formal evidence to support their relative efficacy and toxicity claims. The reasons for the lack of robust evaluation of these new technologies are valid. Studies to demonstrate improved efficacy are lengthy and costly. Given the favorable prognosis of patients in this category, efficacy often cannot be determined for many years if ever. The proliferation of these methods—and the claims of efficacy and reduced morbidity—are creating confusion in the health care community and among patients. The landscape of therapy for men with low-risk prostate cancer has become a contest among costly, competing technologies without supporting rationale. These technologies require a framework to test their validity (Figure 1). Central to this framework is acceptance of the principle of “incremental gain.” Although the principle may appear self-evident, the allure of new technology has proved difficult to resist. As a consequence, “feasibility” with limited evidence of safety and efficacy has often been regarded as sufficient for clinical application. A framework to guide development and establish criteria for the acceptance of new technologies is required to establish order from chaos. Three broad criteria must be considered in this framework: (1) improved efficacy, (2) improved morbidity profile (complications), and (3) broader health care considerations such as ease of application, training, and cost. It is beyond the scope of this Commentary to comprehensively review data or to make comparisons among the many new technologies. I provide here selected examples of technologies that have achieved a level of clinical application in localized prostate cancer. My goal is to illustrate how the information promoted by these technologies is insufficient for physicians and patients to make knowledgeable decisions about care. It is my hope that the resulting discussion will prompt the development of an efficient and methodical approach to the application of new technologies in prostate cancer therapy. Figure 1 Establishes a framework to guide investigators through initial development and feasibility testing with specific milestones for each category. Critical to success is establishing by criteria and stage of therapy development the pragmatic milestones that ...

Risk of Death From Prostate Cancer After Radical Prostatectomy or Brachytherapy in Men With Low or Intermediate Risk Disease

Radical prostatectomy and brachytherapy are widely used treatments for favorable risk prostate cancer. We estimated the risk of prostate cancer specific mortality following radical prostatectomy or brachytherapy in men with low or intermediate risk prostate cancer using prospectively collected data. The study cohort comprised 5,760 men with low risk prostate cancer (prostate specific antigen 10 ng/ml or less, clinical category T1c or 2a and Gleason score 6 or less), and 3,079 with intermediate risk prostate cancer (prostate specific antigen 10 to 20 ng/ml, clinical category T2b or T2c, or Gleason score 7). Competing risks multivariable regression was performed to assess the risk of prostate cancer specific mortality after radical prostatectomy or brachytherapy, adjusting for age, year of treatment, cardiovascular comorbidity and known prostate cancer prognostic factors. After a median followup of 4.2 years (IQR 2.0-7.4) for low risk and 4.8 years (IQR 2.2-8.1) for intermediate risk men, there was no significant difference in the risk of prostate cancer specific mortality among low risk (adjusted hazard ratio 1.62, 95% CI 0.59-4.45, p = 0.35) or intermediate risk men (AHR 2.30, 95% CI 0.95-5.58, p = 0.07) treated with brachytherapy compared with radical prostatectomy. The only factor associated with an increased risk of prostate cancer specific mortality (AHR 1.05, 95% CI 1.01-1.10, p = 0.03) was increasing age at treatment in intermediate risk men. The risk of prostate cancer specific mortality in men with low or intermediate risk prostate cancer was not significantly different following radical prostatectomy vs brachytherapy.

High-Dose-Rate Brachytherapy as a Monotherapy for Favorable-Risk Prostate Cancer: A Phase II Trial

There are multiple treatment options for favorable-risk prostate cancer. High-dose-rate (HDR) brachytherapy as a monotherapy is appealing, but its use is still investigational. A Phase II trial was undertaken to explore the value of such treatment in low-to-intermediate risk prostate cancer. This was a single-institution, prospective study. Eligible patients had low-risk prostate cancer features but also Gleason scores of 7 (51% of patients) and stage T2b to T2c cancer. Treatment with HDR brachytherapy with a single implant was administered over 2 days. One of four fractionation schedules was used in a dose escalation study design: 3 fractions of 10, 10.5, 11, or 11.5 Gy. Patients were assessed with the Common Terminology Criteria for Adverse Events version 2.0 for urinary toxicity, the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer scoring schema for rectal toxicity, and the Expanded Prostate Cancer Index Composite (EPIC) questionnaire to measure patient-reported health-related quality of life. Biochemical failure was defined as a prostate-specific antigen (PSA) nadir plus 2 ng/ml. Between 2003 and 2008, 79 patients were enrolled. With a median follow-up of 39.5 months, biochemical relapse occurred in 7 patients. Three- and 5-year actuarial biochemical control rates were 88.4% (95% confidence interval [CI], 78.0-96.2%) and 85.1% (95% CI, 72.5-94.5%), respectively. Acute grade 3 urinary toxicity was seen in only 1 patient. There was no instance of acute grade 3 rectal toxicity. Rates of late grade 3 rectal toxicity, dysuria, hematuria, urinary retention, and urinary incontinence were 0%, 10.3%, 1.3%, 9.0%, and 0%, respectively. No grade 4 or greater toxicity was recorded. Among the four (urinary, bowel, sexual, and hormonal) domains assessed with the EPIC questionnaire, only the sexual domain did not recover with time. HDR brachytherapy as a monotherapy for favorable-risk prostate cancer, administered using a single implant over 2 days, is feasible and has acceptable acute and late toxicities. Further follow-up is still required to better evaluate the efficacy of such treatment.

Treatment of Favorable-Risk Prostate Cancer

Treatment of Favorable-Risk Prostate Cancer

Surgically-Derived Nomogram Predicts High Likelihood of Gleason Score Upgrading for Favorable Risk Prostate Cancer Treated With Permanent Seed Brachytherapy at Princess Margaret Hospital

Surgically-Derived Nomogram Predicts High Likelihood of Gleason Score Upgrading for Favorable Risk Prostate Cancer Treated With Permanent Seed Brachytherapy at Princess Margaret Hospital David Bowes, Juanita Crook, Kris Wallace, Andrew Evans, Ants Toi, Antonio Finelli, Michael Jewett. British Columbia Cancer Agency, Kelowna, BC, Canada; Princess Margaret Hospital, Toronto, ON, Canada; University Health Network, Toronto, ON, Canada.

Use of a surgically derived nomogram to predict high likelihood of Gleason score upgrading for favorable-risk prostate cancer treated with permanent seed brachytherapy.

114 Background: Crook et al have reported a 7-year disease-free survival (DFS) of 95.2% in 1,111 men with prostate cancer treated with Iodine-125 permanent seed brachytherapy (BT) at Princess Margaret Hospital. Two nomograms have been developed that estimate the likelihood of Gleason score (GS) upgrading for patients with favorable risk prostate cancer undergoing radical prostatectomy (RP). The purpose of this project was to apply these nomograms to a cohort treated with BT. Methods: Records were examined for all men receiving prostate BT in 2006-7. 217 had favorable risk disease. The likelihood of GS upgrading was predicted using RP-derived nomograms created by Kulkarni et al (PMH, 2007) and Budaus et al (2010). Clinical and pathologic information were available on 208 patients to allow completion of the Kulkarni nomogram, and on 193 patients for the Budaus nomogram. Results: The median age of the BT cohort was 62 years (range 44–77), and the median PSA level 4.68 ng/ml. Clinical stage was T1 in 65%, and 47.6% had positive findings on transrectal ultrasound. Median prostate volume was 33.3 cc (15.0–72.3). Uro-pathology review was available for 93%. 84.1% had extended biopsies, with 40.9% showing prostatic intraepithelial neoplasia and 10.1% inflammation. The median % of positive cores was 25%, with a median maximum % involvement per core of 20%. Two men received androgen deprivation therapy for prostate downsizing. The median predicted likelihood of GS upgrading was 51.6% using the Kulkarni nomogram, and 43.6% using the Budaus nomogram. The median PSA after 3.2 years median follow-up is 0.18 ng/mL. Conclusions: In a population of men with favorable risk prostate cancer treated with BT, the estimated likelihood of GS upgrading using two surgical nomograms was substantial. The study cohort was taken from a larger population of patients treated over 10 years for whom 7-year DFS is 95.2%. This suggests that permanent seed brachytherapy is a highly effective treatment option for patients with favorable risk disease despite unfavorable clinical and pathologic factors. Patients should not be discouraged from brachytherapy on the basis of a high likelihood of GS upgrading. No significant financial relationships to disclose.

Risk of death from prostate cancer after radical prostatectomy or brachytherapy in men with low- or intermediate-risk disease.

198 Background: Radical prostatectomy (RP) and brachytherapy (BT) are widely utilized treatments for favorable-risk prostate cancer (PC). We estimated the risk of PC-specific mortality (PCSM) following RP or BT in men with low- or intermediate-risk PC using prospectively collected data. Methods: The study cohort comprised 5,760 men with low-risk PC (prostate-specific antigen [PSA] level ≤ 10 ng/mL, clinical category T1c or 2a, and Gleason score ≤ 6), and 3,079 men with intermediate-risk PC (PSA level 10-20 ng/mL, clinical T2b or T2c, or Gleason score 7). Competing risks multivariable regression was performed to assess risk of PCSM after RP or BT, adjusting for age, treatment year, cardiovascular comorbidity, and known PC prognostic factors. Results: There was no significant difference in the risk of PCSM among men with low-risk PC (11 vs. 6 deaths: adjusted hazard ratio [AHR], 1.62; 95% CI, 0.59–4.45; P = 0.35) who received BT compared to RP. However among men with intermediate-risk PC, despite significantly shorter median follow-up for men undergoing BT as compared to RP (4.1 vs. 7.2 years, P < 0.001), there was a trend toward an increased risk of PCSM (18 vs. 9 deaths: AHR, 2.30; 95% CI, 0.95–5.58; P = 0.07) for men treated with BT. Conclusions: The risk of PCSM among men with low-risk PC was not significantly different following RP or BT, however there may be a reduced risk of PCSM after RP as compared to BT in men with intermediate-risk PC. [Table: see text] No significant financial relationships to disclose.

Comparison of Tumor Control and Toxicity Outcomes of High-dose Intensity-modulated Radiotherapy and Brachytherapy for Patients With Favorable Risk Prostate Cancer

To compare the long-term, prostate-specific antigen relapse-free survival outcome and incidence of toxicity for patients with low-risk prostate cancer who underwent brachytherapy or intensity-modulated radiotherapy (RT). A total of 729 consecutive patients underwent brachytherapy (n = 448; prescription dose 144 Gy) or intensity-modulated RT alone (n = 281; prescription dose 81 Gy). The prostate-specific antigen relapse-free survival using the nadir plus 2 ng/mL definition and late toxicity using the National Cancer Institute's Common Terminology Criteria for Adverse Events were determined. The 7-year prostate-specific antigen relapse-free survival rate for the brachytherapy and intensity-modulated RT groups was 95% and 89% for low-risk patients, respectively (P = .004). Cox regression analysis demonstrated that brachytherapy was associated with improved prostate-specific antigen relapse-free survival, even after adjustment for other variables. The incidence of metastatic disease between treatment sessions was low for both treatment groups. Late grade 2 gastrointestinal toxicity was observed in 5.1% and 1.4% of the brachytherapy and intensity-modulated RT groups, respectively (P = .02). No significant differences were seen between treatment groups for late grade 3 or greater rectal complications (brachytherapy 1.1% and intensity-modulated RT 0%; P = .19). Late grade 2 urinary toxicity occurred more often in the brachytherapy group than in the intensity-modulated RT group (15.6% and 4.3%, respectively; P < .0001). No significant differences were seen between the 2 treatment groups for late grade 3 urinary toxicity (brachytherapy 2.2% and intensity-modulated RT 1.4%; P = .62). Among low-risk prostate cancer patients, the 7-year biochemical tumor control was superior for intraoperatively planned brachytherapy compared with high-dose intensity-modulated RT. Although significant toxicities were minimal for both groups, modest, but significant, increases in grade 2 urinary and rectal symptoms were noted for brachytherapy compared with intensity-modulated RT.

Nutritional supplements, COX-2 and IGF-1 expression in men on active surveillance for prostate cancer

BackgroundNutritional factors are associated with reduced risk of prostate cancer progression, yet mechanisms remain unclear. We examined the effects of lycopene and fish oil supplements versus placebo on the normal prostate microenvironment, among men pursuing active surveillance for low-burden prostate cancer. We hypothesized that lycopene or fish oil supplements would down-regulate insulin-like growth factor-1 (IGF-1) and cyclooxygenase 2 (COX-2) gene expression, respectively, reflecting putative proliferation (IGF-1) and inflammatory (COX-2) pathways relevant to carcinogenesis.MethodsWe conducted a 3-month randomized, double-blinded, clinical trial comparing prostate tissue gene expression profiles (assessed by qRT–PCR) among men with favorable-risk prostate cancer receiving either 30 mg/day lycopene, 3 g/day fish oil (including 1,098 mg eicosapentaenoic and 549 mg docosahexaenoic fatty acids) or placebo.ResultsAmong 69 men (22 assigned to lycopene, 21 to fish, and 26 to placebo), there was no difference in the change from baseline to the 3 months in IGF-1 expression level between the placebo and lycopene arms (p = 0.93) nor in COX-2 expression between the placebo and fish arms (p = 0.99).ConclusionCompared to placebo, 3-month intervention with lycopene or fish oil did not significantly change IGF-1 and COX-2 gene expression in the normal prostate microenvironment in men with low-burden prostate cancer. Further analysis of global gene expression profiles may shed light on the bioactivity and relevance of these nutrients in prostate cancer.

Searching for Optimal Dose–Volume Constraints to Reduce Rectal Toxicity after Hypofractionated Radiotherapy for Prostate Cancer

Aims Late rectal toxicity is a major concern for prostate cancer patients treated with radiotherapy. Rectal dose–volume constraints, set as guidelines to reduce its incidence, vary among institutions. From a group of patients uniformly treated with hypofractionated radiotherapy, we correlated the incidence of late rectal toxicity with rectal dose–volume rectal constraints as described in three randomised trials for prostate cancer. Materials and methods Favourable-risk prostate cancer patients received a dose of 66 Gy in 22 fractions without hormonal therapy. Toxicity was prospectively assessed using Common Toxicity Criteria v3. The whole or part of the rectum and rectal wall were contoured as an organ at risk for all patients. The rectal constraints of the RTOG 0126, RTOG 0415 and the PROFIT trials were used to correlate with late rectal toxicity. Results The median follow-up time was 58 months. Late rectal toxicity was 62, 20 and 18% for grades 0, 1 and 2/3, respectively. No statistically significant correlation was found between late rectal toxicity and the rectal constraints used in the three trials. The number of patients violating the recommended constraints was similar for the group with grade 2/3 toxicity and the group without any toxicity. Analysis derived from the actual dose–volume histogram dose parameters of this group of patients did not show a relationship between dose to volume of the rectum and late rectal toxicity that could generate a guideline of dose constraints. Conclusion For this group of patients, despite the use of recognised dose–volume constraint guidelines of three trials, we were unable to establish a relationship between these constraints and the late rectal toxicity registered. Further studies on the correlation of dosimetric parameters with rectal toxicity, particularly for hypofractionated regimens, are required. Non-dosimetric factors may also be involved in the risk of late rectal toxicity.

Reply to P.B. Singh et al

Drs Singh, Ahmed, and Emberton have expressed quite clearly the conundrum at the heart of conservative management. Accurate characterization of disease aggressivity is the key to safe and successful management of favorable-risk prostate cancer patients, most of whom are not destined to have clinical progression during their lifetime. We agree that more precise tools to identify the “bad actors” will enhance the appeal of surveillance and improve the results. For example, recent evidence suggests that many patients who harbor higher-grade cancer missed on the original peripheral zone biopsy have sizable anterior lesions. The question now is not whether to do surveillance but how to do it better. We differ with the authors who describe the current attributes of active surveillance as “not particularly attractive.” Multiparametric magnetic resonance imaging, transperineal mapping/saturation biopsies, and genomic/proteomic correlative studies need to be evaluated as strategies to improve patient selection for surveillance. However, we believe that the reported results of current surveillance series, enhanced by strategies including repeat biopsy directed at the anterior prostate and antero-lateral horn at 1 year and periodically thereafter, make surveillance both attractive and compelling to patients who understand the natural history of favorable-risk disease.

Androgen‐suppression therapy for prostate cancer and the risk of death in men with a history of myocardial infarction or stroke

To examine the effect of short-course androgen-suppression therapy (AST) before brachytherapy on all-cause mortality (ACM) rates, stratified by the presence or absence of a history of myocardial infarction (MI) or stroke. AST is used to reduce prostate size to enable men with favourable-risk prostate cancer to undergo brachytherapy, but no disease-specific benefit has been reported for this practice, and AST use has been associated with an increased risk of ACM in some men with pre-existing cardiovascular disease. The study comprised 12792 men with favourable-risk disease, i.e. a prostate-specific antigen (PSA) level of <20 ng/mL, Gleason score ≤7 and clinical category ≤T2c, treated between 1991 and 2007 at community-based medical centres with brachytherapy ± neoadjuvant AST. Multivariable Cox regression analysis was used to assess whether there were significant associations between AST use in men with a history of MI or stroke and the risk of ACM, adjusting for age, treatment year, and known prognostic factors of prostate cancer. After a median (interquartile range) follow-up of 3.8 (2.0-5.9) years there were 1557 deaths. The risk of ACM was lower in men with no history of MI or stroke than in those with this history, whether AST was used (adjusted hazard ratio 0.79, 95% confidence interval 0.67-0.92; P= 0.003) or not (0.74, 0.65-0.85; P < 0.001). However, men with a history of MI or stroke treated with AST had a greater risk of ACM than those not treated with AST (1.2, 1.05-1.38; P= 0.008). The use of short-course AST in men with a history of MI or stroke is associated with a greater risk of ACM in men with favourable-risk prostate cancer.

Reply

The objective of our study was to examine whether men with newly diagnosed “low-risk” prostate cancer as determined from the serum prostate-specific antigen (PSA) levels, digital rectal examination, and biopsy Gleason score, truly have “low-risk” disease. Our findings are relevant to the increasing number of men with newly diagnosed “low-risk” disease who must decide whether to pursue curative intervention and risk the “unnecessary” complications of treatment or elect a “surveillance” strategy and risk missing the window of opportunity to cure the disease and therefore suffer the “avoidable” ravages of prostate cancer. To scare all these men into active treatment by arguing that prostate cancer is invariably a lethal disease that must be eradicated at all costs to avoid a miserable demise is indefensible. Our findings suggest that it is equally irresponsible to assure these men they have a benign form of cancer and that delaying curative intervention will be associated with absolutely no consequences. Editorial CommentUrologyVol. 76Issue 3PreviewThis well-documented cohort is one of several recent papers addressing the pathologic findings at prostatectomy in men who were diagnosed with favorable-risk prostate cancer and are therefore potential candidates for surveillance.1-8 Like other studies, the authors report that a proportion of favorable-risk patients harbor higher-risk disease. They express caution about the role of surveillance because of this uncertainty, particularly in young men. Full-Text PDF

Active Surveillance for Prostate Cancer: Patient Selection and Management

Screening for prostate cancer using prostate-specific antigen (PSA) has been appealing. However, the significant associated decline in prostate cancer mortality comes at the cost of a very high rate of diagnosis, and many patients with indolent, non-life-threatening cancer are exposed to the risk of significant side effects from radical treatment. Most men with favourable-risk prostate cancer are not destined to die of their disease, even in the absence of treatment. The challenge is to identify the subset that harbour more aggressive disease early enough that curative therapy is still a possibility, thereby allowing the others to enjoy improved quality of life, free from the side effects of treatment. This article reviews current research into active surveillance in favourable-risk disease and some of the issues that arise when prostate cancer is monitored rather than being treated immediately.

Editorial Comment

This well-documented cohort is one of several recent papers addressing the pathologic findings at prostatectomy in men who were diagnosed with favorable-risk prostate cancer and are therefore potential candidates for surveillance. 1 Ploussard G. Salomon L. Xylinas E. et al. Pathological findings and prostate specific antigen outcomes after radical prostatectomy in men eligible for active surveillance-does the risk of misclassification vary according to biopsy criteria?. J Urol. 2010; 183: 539-544 Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar , 2 Suardi N. Briganti A. Gallina A. et al. Testing the most stringent criteria for selection of candidates for active surveillance in patients with low-risk prostate cancer. BJU Int. 2010; 105: 1548-1552 Crossref PubMed Scopus (48) Google Scholar , 3 Azancot V. Peyromaure M. Xylinas E. et al. Analysis of anatomopathological results of radical prostatectomy specimen of patients who answer to criteria for active surveillance of prostate cancer. Prog Urol. 2009; 19: 619-623 Crossref PubMed Scopus (7) Google Scholar , 4 Duffield A.S. Lee T.K. Miyamoto H. et al. Radical prostatectomy findings in patients in whom active surveillance of prostate cancer fails. J Urol. 2009; 182: 2274-2278 Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar , 5 Louie-Johnsun M. Neill M. Treurnicht K. et al. Final outcomes of patients with low-risk prostate cancer suitable for active surveillance but treated surgically. BJU Int. 2009; 104: 1501-1504 Crossref PubMed Scopus (38) Google Scholar , 6 Conti S.L. Dall'era M. Fradet V. et al. Pathological outcomes of candidates for active surveillance of prostate cancer. J Urol. 2009; 181: 1628-1633 Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar , 7 Kvåle R. Møller B. Wahlqvist R. et al. Concordance between Gleason scores of needle biopsies and radical prostatectomy specimens: A population-based study. BJU Int. 2009; 103: 1647-1654 Crossref PubMed Scopus (173) Google Scholar , 8 Kulkarni G.S. Lockwood G. Evans A. et al. Clinical predictors of Gleason score upgrading: Implications for patients considering watchful waiting, active surveillance, or brachytherapy. Cancer. 2007; 109: 2432-2438 Crossref PubMed Scopus (95) Google Scholar Like other studies, the authors report that a proportion of favorable-risk patients harbor higher-risk disease. They express caution about the role of surveillance because of this uncertainty, particularly in young men. Pathologic Outcomes of Candidates for Active Surveillance Undergoing Radical ProstatectomyUrologyVol. 76Issue 3PreviewTo examine the pathologic findings and biochemical recurrence rates for a consecutive cohort of candidates for active surveillance who underwent radical prostatectomy. The role of active surveillance for the treatment of low-risk prostate cancer is highly controversial. Full-Text PDF ReplyUrologyVol. 76Issue 3PreviewThe objective of our study was to examine whether men with newly diagnosed “low-risk” prostate cancer as determined from the serum prostate-specific antigen (PSA) levels, digital rectal examination, and biopsy Gleason score, truly have “low-risk” disease. Our findings are relevant to the increasing number of men with newly diagnosed “low-risk” disease who must decide whether to pursue curative intervention and risk the “unnecessary” complications of treatment or elect a “surveillance” strategy and risk missing the window of opportunity to cure the disease and therefore suffer the “avoidable” ravages of prostate cancer. Full-Text PDF

Hypofractionated Radiotherapy for Favorable Risk Prostate Cancer

Since the recognition that prostate cancer probably has a low alpha/beta ratio, hypofractionated radiotherapy has become an attractive treatment option for localized prostate cancer. However, there is little experience with the use of hypofractionation delivering a high biologically equivalent dose. We report our experience with high-dose hypofractionated radiotherapy. A total of 129 patients with favorable risk prostate cancer were treated with three-dimensional conformal radiotherapy treatment plans to the dose of 66 Gy in 22 fractions, prescribed at the isocenter. Planning target volume consisted of the prostate plus a uniform 7-mm margin, including the rectal margin. No patient received hormonal therapy. Toxicity was prospectively graded by the Common Toxicity Criteria version 3. Biochemical relapse was defined as postradiotherapy nadir prostate-specific antigen + 2 ng/mL. With a median follow-up of 51 months, the 5-year actuarial biochemical control rate is 98%. The only 3 cases with biochemical failure did not have a clinical local relapse. More than 50% of patients did not develop acute toxicity. For late toxicity, the worst crude rate of Grade >or=2 genitourinary (GU) and gastrointestinal (GI) toxicity seen at any time during follow-up were 32% and 25%, respectively. There was no Grade 4 or 5 toxicity. At the last follow-up, persistent Grade >or=2 late GU and GI toxicity were 2% and 1.5%, respectively. This hypofractionated regimen provides excellent biochemical control in favorable risk prostate cancer with an acceptable rate of late toxicity. Further studies exploring this hypofractionation regimen are warranted.

Prostate Cancer Death of Men Treated With Initial Active Surveillance: Clinical and Biochemical Characteristics

Active surveillance for favorable risk prostate cancer is an approach that may reduce the risk of overtreatment of clinically insignificant prostate cancer. In fact, some patients with favorable risk disease at diagnosis harbor more aggressive disease and may be at risk for prostate cancer mortality despite close monitoring. This is a detailed report of 5 of 453 patients on surveillance who died of prostate cancer. A large phase 2 prospective trial of active surveillance in patients with favorable risk prostate cancer was initiated in 1995. Eligible patients had favorable risk prostate cancer (prostate specific antigen 10 ng/ml or less, Gleason 6 or less, T1c/T2a). Epstein criteria for clinically insignificant prostate cancer (a third or less of cores positive, 50% or less involvement of any 1 core, and prostate specific antigen density less than 0.15) were used for men younger than 55 years. Patients were followed with serial prostate specific antigen determinations every 3 months for 2 years and then every 6 months if stable. Biopsies were performed at 1 year and then every 3 to 4 years. Radical intervention was offered if prostate specific antigen doubling time was less than 3 years or Gleason 3 + 4 pattern disease was identified on repeat biopsy. For the first 5 years of the study patients older than 70 years were eligible if they had Gleason 3 + 4 or less, or prostate specific antigen less than 15 ng/ml. The rate of intervention with radiation or surgery was 38% at 10 years (actuarial). All 5 patients had a prostate specific antigen doubling time of 1.6 years or less triggering a recommendation of radical therapy. Radical intervention was performed in 3 of the 5 patients. Patients 1 and 4 received radiation and patient 3 underwent radical prostatectomy. Of the 2 patients who did not receive definitive treatment 1 was lost to followup (patient 2) and was treated conservatively by his family doctor. Patient 5 elected androgen deprivation therapy rather than radical treatment. The low prostate cancer mortality in our surveillance cohort provides support for an active surveillance approach to favorable risk prostate cancer. Only 1 of the 5 patients presented with favorable disease and experienced a theoretically preventable death. The absence of preventable deaths suggests that the basic approach is sound. Two patients had a trigger for intervention but did not receive it. This reinforces the importance of close monitoring and of definitive treatment for those in whom disease is reclassified as higher risk over time.

3D MR-Spectroscopic Imaging Assessment of Metabolic Activity in the Prostate During the PSA “Bounce” Following 125Iodine Brachytherapy

A temporary increase in prostate-specific antigen (PSA) values is observed in 30%-40% of men following (125)I brachytherapy (BT) for prostate cancer. We present the results of a study to characterize prostate metabolic activity during the PSA "bounce" and to correlate metabolic changes with PSA levels using three-dimensional magnetic resonance spectroscopic imaging (3D-MRSI). 3D-MRSI was performed in 24 patients during the PSA bounce. Eight of these had also had a baseline 3D-MRSI scan before BT for the purpose of tumor mapping. The 3D-MRSI was repeated at 6- and 12-month intervals, and PSA levels were monitored every 3 months. Twenty-one of the patients had favorable-risk prostate cancer, and 3 had intermediate risk. The choline+creatine signal intensity, although markedly reduced, was observable following BT. Diffuse activity not corresponding to original biopsy-positive sites was observed in 22 cases, and 2 cases were documented to have local recurrence. No statistically significant correlation between metabolic activity and PSA levels at each interval was found. Post-BT prostate 3D-MRSI shows evidence of diffuse metabolic activity unrelated to residual malignancy. This supports the benign nature of the PSA bounce and suggests an inflammatory etiology. In the situation of a rising PSA, observation of focal activity on MRI/3D-MRSI could be a useful adjunct to suggest local recurrence at an earlier interval after brachytherapy when prostate biopsies would still be unhelpful. Longer follow-up is necessary to confirm the complex relationship between metabolic activity and PSA levels.

Active Surveillance for Prostate Cancer: A Review

Active surveillance is a solution to the widely acknowledged problem of overdiagnosis and overtreatment of clinically insignificant disease which accompanies early detection of prostate cancer using prostate-specific antigen (PSA) and biopsy. It is an approach to the management of favorable-risk prostate cancer which uses the opportunity provided by the long natural history of the disease to incorporate a period of initial observation into patient management. The basic concept is that most men diagnosed with low-grade, small-volume disease are not destined to have any clinical manifestations of the condition during their lifetime. However, a subset of patients with favorable-risk prostate cancer is at risk, due to either the presence of higher-risk disease not apparent at diagnosis or progression to a more aggressive phenotype over time. These patients can be identified with reasonable accuracy by close follow-up, including serial PSAs and biopsies, and treated effectively in most cases. The rationale, patient selection, method of follow-up, triggers for intervention, and recent results of this approach will be reviewed.

Active surveillance for favorable-risk prostate cancer: a short review.

Active surveillance is becoming a more widely accepted management strategy in men with low-risk localized prostate cancer. This is in recognition of the knowledge that most men with such cancer are likely to die from other causes. The obvious benefits of active surveillance are reduced morbidity by delaying or avoiding radical gland therapy. These advantages should be balanced against appropriate selection criteria and triggers for moving to radical therapy while on active surveillance. The optimal method by which to identify the small number of men who will progress by use of clinical, biopsy, and imaging data is yet to be defined. Nevertheless, active surveillance is an appealing management option in selected men with prostate cancer and represents a solution to the significant problem of the overdiagnosis of clinically insignificant disease that accompanies prostate-specific antigen (PSA) screening.