PSA doubling time in prostate cancer relapsed after endocrine therapy

PURPOSE: The PSA level of prostate cancer patients generally declines after endocrine therapy, but elevates when the cancer relapses in most cases. However, the rate of elevation differs with the case. We investigated the PSA doubling time (PSA-DT) of the prostate cancer patients whose PSA declined after endocrine therapy and later re-elevated, and investigated the relationship with other parameters. PATIENTS AND METHODS: We investigated 55 prostate cancer patients who underwent endocrine therapy between 1991 and 1998. Their PSA re-elevated continuously after their PSA fell below 10 ng/ml after the endocrine therapy as the first line treatment. First, the correlation coefficients with time and PSA were calculated in order to decide whether their PSA elevation was exponential or linear. PSA-DT was calculated thereafter, and compared with the clinical stage, pathological differentiation, clinical relapse style, time from the beginning of the therapy to PSA relapse, pre-treatment PSA value, and prognosis. The relationship between PSA-DT and each clinical parameter was tested using the Kruskal-Wallis test. Differences in survival rates and PSA-DT were calculated using the log-rank test. RESULTS: PSA elevated exponentially after cancer relapsed. PSA-DT in all cases ranged from 0.5 to 26.3 months, with an average of 4.4 +/- 4.8 (S.D.) months and the median was 2.5 months. PSA-DT was significantly (p < 0.01) short when the pre-treatment clinical stage was high, the time from the beginning of the therapy to PSA relapse was short, or the pre-treatment PSA value was high. PSA-DT tended to be short when the pre-treatment pathological differentiation was low, but not significantly. PSA-DT tended to be short when the cancer relapsed as distant metastasis rather than regional relapse, but not significantly. Prognosis from the initial treatment and PSA relapse was significantly poor when the PSA-DT was short. CONCLUSIONS: PSA elevated exponentially in the relapsed prostate cancer patients after the endocrine therapy. PSA-DT was distributed in a very wide range, and this value was considered to reflect the malignant potential and prognosis of the cancer. PSA-DT may be useful for determining the strategy after relapse.     

Utility of prostate specific antigen doubling time in repeat biopsy for prostate cancer

PURPOSE: It is not rare that the repeat biopsy is performed when the initial biopsy was negative. However, there is not a clear indication for the repeat biopsy. We evaluated the utility of prostate specific antigen doubling time (PSA-DT) as indication for the repeat biopsy. MATERIALS AND METHODS: Of men 103 underwent repeat biopsy after initial negative prostate biopsy, 55 men who had three or more serial PSA measurements until repeat biopsy were evaluated. PSA-DT was calculated using a log-linear regression model and compared with other PSA-related parameters. RESULTS: Prostate cancer was diagnosed in 22 patients (40.0%). Mean PSA-DT in 55 patients was 59.3 months. Comparing of repeat positive biopsy group and negative group, PSA density (PSAD) and PSA velocity (PSAV) in the positive biopsy group were significantly greater than in the negative biopsy group. Age, serum PSA concentration at initial and repeat biopsy, PSA adjusted for volume of transition zone (PSATZ), free to total PSA ratio (%F/T) did not recognize significant differences between both biopsy groups. PSA-DT of positive biopsy group (35.1 months) was significantly shorter than that of negative biopsy group (76.5 months). None was diagnosed prostate cancer whose PSA-DT was longer than 96 months. CONCLUSION: When we considered prostate repeat biopsy, it was thought that PSA-DT could be one important material, but it was limitation for indication as to other PSA-related parameters.     

PSA-related parameters in prostate cancer relapsed after endocrine therapy

PURPOSE: Prostate cancer is generally controlled by endocrine therapy even in an advanced state, but relapse may occur in many cases. Generally, the prognosis of a relapsed case is poor, but the prognosis differs case by case. We experienced 74 cases of prostate cancer relapsed after effective endocrine therapy, and investigated the relationship between the PSA-related parameters, clinical stage and prognosis. PATIENTS AND METHODS: We investigated 74 prostate cancer patients whose PSA declined 10 ng/ml or lower by the treatment consisting of endocrine therapy, but relapsed later. Pre-treatment PSA, the value of PSA nadir, the period from the start of treatment to PSA nadir, the period from the start of treatment to relapse, PSA doubling time (PSA-DT) at relapse and PSA response to the second line therapy at relapse were calculated, and compared with the clinical stage and prognosis. The relationship between each PSA parameter and clinical stage was tested using the Kruskal-Wallis test and chi 2 test. Cancer-specific survival after relapse in stage D patients was calculated by the Kaplan-Meier method and differences in prognosis were tested using the Logrank test. RESULTS: Pre-treatment PSA was significantly (p < 0.01) high, while the period from the start of treatment to relapse (p < 0.05) and PSA-DT at relapse (p < 0.01) was significantly short as the stage progressed. According to PSA response to the second line therapy at relapse, the rate of CR + PR was significantly (p < 0.05) high in clinical stage B + C group compared to clinical stage D group. The prognosis after relapse was significantly poorer in patients with relapse within 10 months after start of treatment than in those with relapse later, and in patients whose PSA-DT at relapse was shorter than 2 months than in those with a longer PSA-DT. CONCLUSIONS: The period from the start of treatment to relapse, and PSA-DT at relapse were useful PSA-related parameters for predicting prognosis after relapse, and for determining the strategy of cancer therapy after relapse. Using these data, the physician can inform the family and the patient of the prognosis more accurately, so that they can adjust future plans.     

Surrogate end point for prostate cancer specific mortality in patients with nonmetastatic hormone refractory prostate cancer

PURPOSE: We determined whether prostate specific antigen (PSA) velocity can serve as surrogate end point for prostate cancer specific mortality (PCSM) in patients with nonmetastatic, hormone refractory prostate cancer. MATERIALS AND METHODS: The study cohort comprised 919 men treated from 1988 to 2002 at 1 of 44 institutions with surgery (560) or radiation therapy (359) for clinical stages T1c-4NxMo prostate cancer, followed by salvage hormonal therapy for PSA failure. All patients experienced PSA defined recurrence while on hormonal therapy. Prentice criteria require that the surrogate should be a prognostic factor and the treatment used did not alter time to PCSM following achievement of the surrogate end point. These criteria were tested using Cox regression. All statistical tests were 2-sided. RESULTS: PSA velocity greater than 1.5 ng/ml yearly was statistically significantly associated with time to PCSM and all cause mortality following PSA defined recurrence while undergoing hormonal therapy (Cox p <0.0001). While initial treatment was statistically associated with time to PCSM and all cause mortality (Cox p = 0.001 and 0.01), this association became insignificant when PSA velocity and potential confounding variables were included in the Cox model (p = 0.22 and 0.93, respectively). The adjusted HR for PCSM in patients who experienced a greater than 1.5 ng/ml increase in PSA within 1 year while on hormonal therapy was 239 (95% CI 10 to 5,549). CONCLUSIONS: These data provide evidence to support PSA velocity greater than 1.5 ng/ml yearly as a surrogate end point for PCSM in patients with nonmetastatic, hormone refractory prostate cancer. Enrolling these men onto clinical trials evaluating the impact of chemotherapy on time to bone metastases and PCSM is warranted.     

Failure patterns and hazard rates for failure suggest the cure of prostate cancer by external beam radiation

OBJECTIVES: To present patterns of failure and hazard rates for failure that support the concept of cure for patients with prostate cancer treated with external beam radiation (RT). METHODS: Two patient groups are reported: 408 patients treated with RT alone and 63 patients treated with RT and short-term androgen deprivation (RT+AD). All patients were treated between March 1987 and March 1995 and had at least 4 years of prostate-specific antigen (PSA) follow-up. The median follow-up was 69 months for the RT alone group and 60 months for the RT+AD group. For each treatment group, biochemical control and hazard functions were estimated using the ASTRO consensus definition of failure and the life table method. RESULTS: The 5 and 8-year biochemical control estimates were 60% and 59% for the RT alone group, respectively, with only two failures occurring after 5 years (1% of the total failures observed). Hazard function estimates indicated a maximum risk of failure at 12 to 36 months, tapering to a low rate at 4 years, with no failures observed after 6 years. The differences in the patterns of failure by PSA level revealed a maximum risk of failure at 12 to 24 months (median 28) for a pretreatment PSA level of less than 10 ng/mL, 12 to 36 months (median 25) for a pretreatment PSA level of 10 to 19.9 ng/mL, and 12 to 36 months (median 22) for a pretreatment PSA level of 20 ng/mL or greater. The latter group reached low levels of risk at 6 years in contrast to 4 years for the patients presenting with pretreatment PSA levels of less than 20 ng/mL. Similar patterns were observed when stratifying by stage and Gleason score: patients with a worse prognosis had the highest risk of failure earlier and achieved a low risk of failure later than patients with a more favorable prognosis. The patients in the RT+AD group had a different pattern of risk of failure, with the highest risk immediately after treatment, declining to a low risk of failure at 48 months. CONCLUSIONS: Patients treated with RT alone or RT+AD had little risk of failure after 4 to 6 years. Patients with a favorable prognosis achieved a low risk of failure sooner than high-risk patients when treated with RT alone. These results are consistent with the cure of prostate cancer by RT alone or RT+AD.     

Secondary therapy, metastatic progression, and cancer-specific mortality in men with clinically high-risk prostate cancer treated with radical prostatectomy

OBJECTIVES: Commonly used definitions for high-risk prostate cancer identify men at increased risk of PSA relapse after radical prostatectomy (RP). We assessed how accurately these definitions identify patients likely to receive secondary cancer therapy, experience metastatic progression, or die of prostate cancer. MATERIALS AND METHODS: Among 5960 men with clinically localized or locally advanced prostate cancer who underwent RP, we identified eight different high-risk subsets, each comprising 4-40% of the study population. Estimates of freedom from radiation therapy, hormonal therapy, and metastatic progression after surgery were generated for each high-risk cohort with the Kaplan-Meier method, and hazard ratios (HR) were calculated with a Cox proportional hazards regression. The cumulative incidence and HR for prostate cancer-specific mortality (PCSM) were estimated with competing risk analysis. RESULTS: Each of the studied high-risk criteria was associated with increased hazard of secondary cancer therapy (HR=1.3-5.2, p<0.05) and metastatic progression (HR=2.1-6.9, p<0.05). However, depending on the definition, the probability of freedom from additional therapy 10 yr after surgery ranged from 35% to 76%. The 10-yr cumulative incidence of PCSM in high-risk patients ranged from 3% to 11% (HR=3.2-10.4, p<0.0005). CONCLUSIONS: Commonly used definitions for high-risk prostate cancer identify men at increased risk of secondary cancer therapy, metastatic progression, and PCSM following RP. However, a substantial proportion of high-risk patients remain free from additional therapy or metastatic disease many years after surgery. The risk of PCSM within 10 yr of treatment is remarkably low, even for patients at the highest risk of recurrent disease.     

Prognostic Value of Biochemical Recurrence Following Treatment with Curative Intent for Prostate Cancer: A Systematic Review

ContextIn men with prostate cancer (PCa) treated with curative intent, controversy exists regarding the impact of biochemical recurrence (BCR) on oncological outcomes.ObjectiveTo perform a systematic review of the existing literature on BCR after treatment with curative intent for nonmetastatic PCa. Objective 1 is to investigate whether oncological outcomes differ between patients with or without BCR. Objective 2 is to study which clinical factors and tumor features in patients with BCR have an independent prognostic impact on oncological outcomes.Evidence acquisitionMedline, Medline In-Process, Embase, and the Cochrane Central Register of Controlled Trials were searched. For objective 1, prospective and retrospective studies comparing survival outcomes of patients with or without BCR following radical prostatectomy (RP) or radical radiotherapy (RT) were included. For objective 2, all studies with at least 100 participants and reporting on prognostic patient and tumor characteristics in patients with BCR were included. Risk-of-bias and confounding assessments were performed according to the Quality in Prognosis Studies tool. Both a narrative synthesis and a meta-analysis were undertaken.Evidence synthesisOverall, 77 studies were included for analysis, of which 14 addressed objective 1, recruiting 20 406 patients. Objective 2 was addressed by 71 studies with 29 057, 11 301, and 4272 patients undergoing RP, RT, and a mixed population (mix of patients undergoing RP or RT as primary treatment), respectively. There was a low risk of bias for study participation, confounders, and statistical analysis. For most studies, attrition bias, and prognostic and outcome measurements were not clearly reported. BCR was associated with worse survival rates, mainly in patients with short prostate-specific antigen doubling time (PSA-DT) and a high final Gleason score after RP, or a short interval to biochemical failure (IBF) after RT and a high biopsy Gleason score.ConclusionsBCR has an impact on survival, but this effect appears to be limited to a subgroup of patients with specific clinical risk factors. Short PSA-DT and a high final Gleason score after RP, and a short IBF after RT and a high biopsy Gleason score are the main factors that have a negative impact on survival. These factors may form the basis of new BCR risk stratification (European Association of Urology BCR Risk Groups), which needs to be validated formally.Patient summaryThis review looks at the risk of death in men who shows rising prostate-specific antigen (PSA) in the blood test performed after curative surgery or radiotherapy. For many men, rising PSA does not mean that they are at a high risk of death from prostate cancer in the longer term. Men with PSA that rises shortly after they were treated with radiotherapy or rapidly rising PSA after surgery and a high tumor grade for both treatment modalities are at the highest risk of death. These factors may form the basis of new risk stratification (European Association of Urology biochemical recurrence Risk Groups), which needs to be validated formally.     

Progression after docetaxel-based chemotherapy in androgen-independent prostate cancer

OBJECTIVE: To assess the clinical pattern of progression and prostate-specific antigen doubling time (PSA-DT) after exposure to docetaxel-based chemotherapy in patients with androgen-independent prostate cancer (AIPC). PATIENTS AND METHODS: Fifty-five patients received docetaxel-based chemotherapy; data were collected retrospectively from three different departments. Progression was known in 44 (79%) and the PSA-DT was available in 33 patients. RESULTS: Of the 29 patients with soft-tissue and soft-tissue plus bone metastases, 22 (76%) developed soft-tissue progression. Among the 35 patients with bone and bone plus soft-tissue metastases, 27 (77%) had osseous progression. There was no difference between the PSA-DT at progression before and after docetaxel-based therapy (mean 3.1 vs 2.7 months, P = 0.592, Student's t-test.). However, the median (range) PSA-DT at progression after docetaxel-based therapy was 0.84 (0.3-4) months in patients with a PSA response, significantly shorter than the median of 3.1 (0.3-12) months of patients with no biochemical response (P = 0.002, Student's t-test). The PSA-DT dynamics at progression had no effect on survival (P = 0.63, log-rank test). CONCLUSION: The pattern of progression after docetaxel-based chemotherapy is predominantly osseous in patient with bone metastases and mostly soft-tissue in those with soft-tissue disease. Progression after docetaxel-based chemotherapy in AIPC does not modify the PSA-DT before docetaxel. Evaluation of a larger population is needed to assess the clinical relevance of PSA dynamics after docetaxel therapy.     

Association of age and response to androgen‐deprivation therapy with or without radiotherapy for prostate cancer: data from CaPSURE

Study Type – Therapy (prospective cohort)
Level of Evidence 2b

OBJECTIVE

To assess whether the response to primary androgen‐deprivation therapy (PADT) and radiotherapy (RT) plus adjuvant ADT would be muted in older men, as their tumours might already be relatively androgen insensitive, because serum testosterone levels decline with increasing age.

PATIENTS AND METHODS

Using the Cancer of the Prostate Strategic Urologic Research Endeavor database, we conducted an observational study evaluating two groups of men treated for prostate cancer from 1995 to 2006. One group of 1748 men was treated with PADT and the second group of 612 men was treated with RT (external beam RT or brachytherapy) with neoadjuvant and/or adjuvant ADT. We tested whether age was a predictor of disease progression in the PADT group and prostate‐specific antigen (PSA) recurrence in the RT + ADT group (Phoenix definition). Secondary outcomes were all cause (ACM) and prostate cancer‐specific mortality (PCSM).

RESULTS

In both univariate and multivariate analysis stratifying by clinical risk group, age (<65, 65–69, 70–74, and ≥75 years) was not associated with the risk of secondary treatment or PSA recurrence for the PADT and the RT + ADT groups, respectively. Age category had no relationship to increased ACM or PCSM for the RT + ADT group. However, for the PADT group the oldest category (>75 years) had an increased hazard ratio (2.26, 95% confidence interval 1.04–4.88; P = 0.02) for ACM, but a decreased ratio for PCSM (0.29, 0.21–0.42; P < 0.01).

CONCLUSION

If we assume that age is a valid proxy measure for free available testosterone levels, then these levels do not seem to affect the likelihood of response to ADT, either used alone or combined with RT.     

Substratification of high-risk localised prostate cancer treated by radical prostatectomy

AIM: To evaluate the clinical outcome of high-risk prostate cancer (PC) treated by radical prostatectomy (RP) according to risk factors. METHODS: Patients with stage cT1-T3 PC were stratified in high and low/intermediate risk groups using D'Amico's criteria: PSA>or=20 ng/ml or Gleason score>or=8 or clinical stage>or=T2c. The Kaplan Meier and Log rank test were used to generate estimates of biochemical free-survival (BFS) and PC specific mortality (PCSM). RESULTS: We analysed 1,109 patients with a median age of 64.1 years, a mean PSA of 12.8 and a median follow-up of 8.18 years (max. 17.5 years). Overall PSA failures (PSAF) were observed in 23.4%, mortality by all causes in 11.4% and PCSM in 2.9%. The 10-year BFS of the 290 high-risk was 45 versus 75.5% for low/intermediate risk patients and the 10-year PCSM was 10.3 versus 1.4%, respectively. Of the 290 high-risk PC, 25% had organ-confined disease at surgery with 28% PSAF compared to 55% PSAF for non-organ-confined PC irrespective of nodal status. High-risk patients with 1 or>or=2 high risk criteria had 2.6 and 3.86 times increased risk of PSAF compared to low/intermediate risk. Ten-year PCSM for PC individual risk criteria was 4.5% for PSA>or=20, 9.2% for stage>or=T2c and 18.2% for Gleason>or=8. CONCLUSION: Patients with high-risk PC treated by RP by experienced surgeons can have a favourable long-term survival. Further substratification should take into account the variable prognostic implication of the different individual risk factors.     

Prognostic factors for PSA relapse of prostate cancer after endocrine therapy

PURPOSE: Advanced prostate cancer responds well to endocrine therapy initially, but soon becomes refractory and has a poor prognosis. We analyzed the prognostic factors of prostate cancer responding well initially to endocrine therapy with lowering of serum prostate specific antigen (PSA) level but later showing PSA relapse. MATERIALS AND METHODS: In prostate cancer patients newly diagnosed from January 1992 to December 2004 at our institution, there were 93 patients in that the PSA level of 10 ng/ml or more before therapy initially dropped below 10 ng/ml by endocrine therapy, but showed PSA relapse thereafter. We investigated the relationship between clinical stage, pathological differentiation, initial PSA, duration between initiation of therapy and PSA nadir, the value of PSA nadir, duration between initiation of therapy and PSA relapse, PSA doubling time (PSA-DT) at relapse, PSA response three months after initiation of second line therapy and prognosis after PSA relapse. RESULTS: In Kaplan-Meier method, between all or some categories investigated showed significant difference in prognosis after PSA relapse. In multivariate analysis, the factors that significantly affected prognosis after PSA relapse were clinical stage, pathological differentiation, PSA nadir value, duration between initiation of therapy and PSA relapse and PSA response three months after initiation of second line therapy. CONCLUSION: We investigated the prognostic factors refractory to endocrine therapy. These results are useful in planning the therapy, and in explaining the status or future prospective of the disease to patients and families.     

Deferred combined androgen blockade therapy using bicalutamide in patients with hormone-refractory prostate cancer during androgen deprivation monotherapy

OBJECTIVE: To assess the effect of adding bicalutamide on serum prostate-specific antigen (PSA) levels in patients with hormone-refractory prostate cancer (HRPC) during androgen deprivation monotherapy (ADMT). PATIENTS AND METHODS: Forty-four patients with HRPC were treated with deferred combined androgen blockade (CAB) therapy, administering bicalutamide 80 mg once daily. HRPC was defined biochemically as three consecutive rises in PSA level during ADMT. The treatment response was defined as a > or = 50% decline in PSA levels. Prognostic values of various pretreatment variables for responsiveness to deferred CAB were determined statistically. When the disease relapsed during deferred CAB, bicalutamide was discontinued and the patients were evaluated for the antiandrogen withdrawal syndrome (AWS). RESULTS: Of the 44 patients, 29 (66%) had a PSA response; the median PSA failure-free survival was 9.2+ months. Biopsy Gleason score was the only pretreatment variable predictive of a PSA response (mean Gleason score 7.9 in responders and 8.7 in nonresponders). The PSA doubling time (PSA-DT) was the only statistically significant variable of PSA failure-free survival in a multivariate analysis. The 1- and 2-year PSA failure-free survival rates were 43% and 31% in patients with a PSA-DT of >4 months, while it was 21% and none, respectively, in those with a PSA-DT of <4 months. Responders to deferred CAB had a statistically longer cancer-specific survival than nonresponders. None of 20 patients who were evaluated for AWS had the condition. CONCLUSIONS: Deferred CAB therapy using bicalutamide is effective in patients with progression during ADMT, particularly in those with lower Gleason score tumours or a longer PSA-DT. AWS after deferred CAB is uncommon.     

Interval to biochemical recurrence following radical prostatectomy does not affect survival in men with low-risk prostate cancer

Objectives

To evaluate the temporal relationship between interval to biochemical recurrence (BCR) following radical prostatectomy (RP) and prostate cancer-specific mortality (PCSM).

Patients and methods

The study comprised of 2,116 men from the Victorian Radical Prostatectomy Register, a whole-of-population database of all RPs performed between 1995 and 2000 in Victoria, Australia. Follow-up prostate-specific antigen and death data were obtained via record linkage to pathology laboratories and the Victorian Registry of Births, Deaths and Marriages. Poisson regression models with PCSM as the outcome were fit to the data. Models included age at surgery, Gleason score and tumour stage as covariates.

Results

Median post-surgery and post-BCR follow-up was 10.3 and 7.5 years, respectively. 695 men (33 %) experienced BCR during follow-up, of which 82 % occurred within 5 years of RP; 66 men died from prostate cancer. Men with combined high Gleason sum (≥4 + 3) and extra-prostatic (≥pT3a) disease had substantially increased mortality rate with early BCR, while those experiencing BCR after a longer interval had significantly lower mortality. Men with combined low Gleason sum (≤3 + 4) and organ-confined disease (≤pT2c) risk disease were not at any substantial risk of death in this time frame regardless of timing of BCR following RP.

Conclusions

This study evaluates the temporal relationship between BCR and PCSM using a whole-of-population cohort of men treated with RP. Men with low-risk features of prostate cancer at time of RP have low mortality even if they experience early BCR. This subgroup may be counselled regarding their favourable long-term prognosis.     

Cause-specific mortality of low and selective intermediate-risk prostate cancer patients with active surveillance or watchful waiting

BackgroundActive surveillance or watchful waiting (AS/WW) is increasingly being used as an alternative strategy to radical prostatectomy or radiation therapy for appropriately selected patients with prostate cancer (PCa). However, the prognosis of low-risk and selective intermediate-risk PCa patients after AS/WW is poorly defined. In this study we reviewed the patients registered in the Surveillance, Epidemiology, and End Results (SEER) Program to establish a competing risk nomogram for the prediction of prostate cancer-specific mortality (PCSM).MethodsThe information of patients undergoing AS/WW in the SEER program from 2004 to 2015 was obtained. All patients were ISUP (International Society of Urological Pathology) grade 1 or 2 PCa and also fulfilled the National Comprehensive Cancer Network’s definition of low-risk PCa [prostate specific antigen (PSA) <10 ng/mL and cT2aN0M0 or less)]. A competing risk nomogram was used to analyze the association of tumor characteristics with PCSM and non-PCSM among the PCa patients with AS/WW. All cases were randomly divided into a training cohort and a validation cohort (1:1). A competing risk nomogram was constructed to predict PCSM in PCa patients with AS/WW. The performance of the PCSM nomogram was evaluated using the concordance index (C-index) and calibration curve.ResultsA total of 30,538 PCa patients were identified as low risk or selective intermediate risk with AS/WW. The 10-year cumulative incidence of death from prostate cancer and death from other cause were 2.8% (95% CI: 2.4–3.1%) and 19.3% (95% CI: 17.8–20.5%), respectively. Variables associated with PCSM included age, marital status, PSA, and ISUP grade. The PCSM nomogram had a good performance in both the training and validation cohorts, with a C-index of 0.744 (95% CI: 0.700–0.781, P<0.001) and 0.738 (95% CI: 0.700–0.777, P<0.001), respectively.ConclusionsOverall, the prognosis was favorable for the low- and selective intermediate-risk PCa patients with AS/WW. The competing risk nomogram yielded a good performance in identifying subgroups of patients with a higher risk of PCSM and potential candidates for AS/WW.     

The risk of death from prostate cancer in men with Gleason score 3+4 prostate cancer treated using brachytherapy with or without a short course of androgen deprivation therapy

ObjectiveWe evaluated whether intermediate-risk factors, in addition to age, were associated with risk of prostate cancer-specific mortality (PCSM) among men with Gleason 3+4 prostate cancer.Materials and methodsWe conducted a prospective cohort study of 1,920 men with Gleason 3+4 adenocarcinoma of the prostate who received brachytherapy (BT) or BT and a median of 4 months of androgen deprivation therapy (ADT). Separate multivariable Fine and Gray competing risks regression models among men treated with BT or BT and ADT were used to assess whether percentage of positive biopsies (PPB), cT2b-T2c stage, prostate-specific antigen (PSA) of 10.1-20.0 ng/ml, and age >70 years (median) were associated with risk of PCSM after adjustment for comorbidity.ResultsAfter median follow-up of 7.8 years, 284 men (14.8%) had died (31 from prostate cancer). For BT alone, increasing PPB, PSA of 10.1–20.0 vs. 4.0–10.0 ng/mL, and age >70 vs. ≤70 were significantly associated with increased risk of PCSM (adjusted hazard ratio 1.015, 95% confidence interval 1.000–1.031, P = 0.048; 5.55, 2.01-15.29, P<0.001; and 3.66, 1.16–11.56, P = 0.03, respectively). The respective results for BT and ADT were 1.009, 0.987-1.031, P = 0.44; 4.17, 1.29–13.50, P = 0.02; and 3.74, 0.87–16.05, P = 0.08.ConclusionAmong men with Gleason score 3+4 prostate cancer treated with BT, the risk of PCSM was elevated in those with PSA of 10.1–20.0 ng/mL and possibly age >70 years, despite the addition of ADT. Should these findings be validated in future studies, then advanced imaging and targeted biopsy of suspicious areas should be investigated in an effort to personalize treatment and minimize the risk of PCSM in these men.     

Correlation of initial PSA level and biopsy features with PSA-doubling time in early stage prostate cancers in Japanese men

OBJECTIVE: To distinguish good candidates for watchful waiting from those who need immediate treatment in localized prostate cancer. METHODS: Prostate specific antigen (PSA)-doubling time (DT) was calculated by a log-linear regression model for 78 patients with clinically localized prostate cancer (T1c: 47, T2a: 6, T2b: 21, and T3: 4) under surveillance. Median observation period was 37.5 months. The first 1-year PSA-DT was compared with the overall PSA-DT in 41 patients who had been under surveillance for more than 3 years. RESULTS: There was significant difference in the PSA-DT distribution between a pooled group of T1c and T2a and a group of T2b and T3 patients (median 58.8 versus 33.3 months, P = 0.0052). A combination of three parameters consisting of initial PSA level less than 10 ng/ml, WHO grade 1, one or two positive core per six to eight systematic biopsy cores with 50% or less cancer involvement significantly correlated with PSA-DT distribution in the T1c plus T2a group (P = 0.0034). The first year assessment of PSA-DT was identical to the overall assessment in 48.8%, 2 years or more in 36.6%, while it was 2 years or less (possibly over-estimated) in 14.6%. CONCLSION: PSA-DT can be predictable to some extent with the initial PSA level and biopsy features in early stage prostate cancers. Prospective study is needed to clarify whether temporary observation together with PSA-DT estimation is a safe strategy and is complementary to clinico-pathological parameters at diagnosis.     

Natural history of biochemical recurrence after radical prostatectomy: risk assessment for secondary therapy

PURPOSE: A persistently elevated or rising serum level of prostate-specific antigen (PSA) after radical prostatectomy is indicative of recurrent prostate cancer. The natural history of PSA-defined biochemical recurrence (BCR) is highly variable. While a rising PSA level universally antedates metastatic progression and prostate cancer-specific mortality (PCSM), it is not a surrogate for these endpoints. Thus, the management of patients with BCR is controversial. METHODS: A literature review was conducted to determine the incidence and natural history of BCR, prognostic factors for clinical progression (CP), and the available evidence supporting local or systemic salvage therapy for these patients. RESULTS: BCR is best defined as two successive PSA levels > or =0.4 ng/ml, as this correlates most accurately with CP. PSA doubling time (PSA-DT) and prostatectomy Gleason score are the variables that best predict the development of distant metastasis and PCSM. Prognostic models based on these and other variables are useful for assessing the need for salvage therapy and the anticipated outcome following local salvage therapy. A treatment algorithm for managing patients with post-prostatectomy BCR was devised. CONCLUSIONS: Management of patients with BCR after prostatectomy continues to be a complex and challenging issue. Improved methods for risk stratification allow for identification of patients who require treatment. Furthermore, these methods aid in determination of the pattern of disease recurrence, thereby guiding treatment modality. Randomized trials are essential to determine the value of local or systemic salvage therapy strategies in this patient population.     

Commentary on “Initial management of prostate-specific antigen-detected,low-risk prostate cancer and the risk of death from prostate cancer.” Aizer AA,Chen MH,Hattangadi J,D'Amico AV. Harvard Radiation Oncology program,Boston, MA.: BJU Int 2013. doi: 10.1111/j.1464-410X.2012.11789.x. [Epub ahead of print]

WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: The recently published Prostate Cancer Intervention versus Observation Trial (PIVOT) did not identify differences in prostate cancer-specific mortality or all-cause mortality among patients with low-risk disease managed conservatively vs those managed definitively; however, recently published data suggest that older men may harbour more aggressive disease than is identified at biopsy owing to sampling error and undergrading. Whether older men with apparent low-risk disease are placed at risk of prostate cancer-specific mortality when managed conservatively remains unknown. The study used population-level data to show that non-curative approaches for older men with low-risk prostate cancer do result in an increased risk of prostate cancer-specific mortality. Differences between our study and the PIVOT trial include the fact that we included a larger sample size, analysed the data using an 'as-treated' approach, and included a healthier cohort of men as evinced by lower 4-year all-cause mortality estimates in our study than in the PIVOT. Our results suggest that older men with apparent low-risk prostate cancer are at risk of undergrading, which probably explains the differences in prostate cancer-specific mortality observed between men managed conservatively vs those managed definitively. Our study suggests that alternative approaches to excluding occult, high grade prostate cancer are needed in such men.ObjectiveTo evaluate whether older age in men with low-risk prostate cancer increases the risk of prostate cancer-specific mortality (PCSM) when non-curative approaches are selected as initial management.Patients and methodsThe study cohort consisted of 27 969 men, with a median age of 67 years, with prostate-specific antigen (PSA)-detected, low-risk prostate cancer (clinical category T1c, Gleason score≤6, and PSA≤10) identified by the Surveillance, Epidemiology and End Results programme between 2004 and 2007. Fine and Gray's competing risk regression analysis was used to evaluate whether management with non-curative vs curative therapy was associated with an increased risk of PCSM after adjusting for PSA level, age at diagnosis and year of diagnosis.ResultsAfter a median follow-up of 2.75 years, 1121 men died, 60 (5.4%) from prostate cancer. Both older age (adjusted hazard ratio [AHR] 1.05; 95% confidence interval (CI) 1.02-1.08; P<0.001) and non-curative treatment (AHR 3.34; 95% CI 1.97-5.67; P<0.001) were significantly associated with an increased risk of PCSM. Men>the median age experienced increased estimates of PCSM when treated with non-curative as opposed to curative intent (P<0.001); this finding was not seen in men≤the median age (P = 0.17).ConclusionPending prospective validation, our study suggests that non-curative approaches for older men with 'low-risk' prostate cancer result in an increased risk of PCSM, suggesting the need for alternative approaches to exclude occult, high grade prostate cancer in these men.     

Prostate-specific antigen velocity based risk-adapted discontinuation of prostate cancer screening in elderly men

Study Type – Prognostic (cohort)
Level of Evidence 2b What’s known on the subject? and What does the study add? Currently, the U.S. Preventive Services Task Force (USPSTF) recommends against PSA screening for prostate cancer in men aged ≥75 years as it concluded that “the harm of screening for prostate cancer in men age ≥75 years may outweigh the potential benefits”. Our findings suggest that elderly men with a PSA velocity of ≥0.45 ng/ml/year have higher risk of death from prostate cancer. Continuing PSA testing may be beneficial for these men.

OBJECTIVE

? To evaluate weather prostate‐specific antigen (PSA) velocity could be used to stratify patients at risk of death from prostate cancer (PCa) and be useful in aiding decision making regarding PSA screening in elderly men, as previous studies have shown that PSA velocity can predict PCa risk.

PATIENTS AND METHODS

? The cohort included 3,525 patients aged ≥ 75 years with two or more PSA tests before a diagnosis of PCa. Cox proportional hazard model was used to evaluate which variables at time of last PSA measurement were associated with death from PCa. ? The rates of death from PCa after diagnosis in different PSA velocity groups were calculated. Kaplan‐Meier and log rank test were used to assess the significant difference in death from PCa after diagnosis, stratified by PSA velocity cutoff.

RESULTS

? On multivariate analysis, men with a PSA velocity of PSA velocity ≥0.45 ng/mL/year had a 4.8‐fold higher risk of death from PCa as compared to men with a PSA velocity of <0.45 ng/mL/year (p value = 0.013). After a median 6.5 (up to 16.9) years of follow‐up from diagnosis, 1.4% of the men with a PSA velocity <0.45 ng/mL/year had died of PCa as compared to 8.7% of those with a PSA velocity ≥0.45 ng/mL/year. ? The cumulative rate of death from PCa after diagnosis, stratified by a PSA velocity of 0.45 ng/mL/year, was statistically different (log rank test, P < 0.001).

CONCLUSION

? Men age ≥ 75 years old with a PSA velocity of <0.45 ng/mL/year are unlikely to die of PCa. It may be safe to discontinue PSA screening in these men.     

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

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