Undetectable ultrasensitive PSA after radical prostatectomy for prostate cancer predicts relapse-free survival

Radical retropubic prostatectomy is considered by many centres to be the treatment of choice for men aged less than 70 years with localized prostate cancer. A rise in serum prostate-specific antigen after radical prostatectomy occurs in 10-40% of cases. This study evaluates the usefulness of novel ultrasensitive PSA assays in the early detection of biochemical relapse. 200 patients of mean age 61. 2 years underwent radical retropubic prostatectomy. Levels < or = 0.01 ng ml-1 were considered undetectable. Mean pre-operative prostate-specific antigen was 13.3 ng ml-1. Biochemical relapse was defined as 3 consecutive rises. The 2-year biochemical disease-free survival for the 134 patients with evaluable prostate-specific antigen nadir data was 61.1% (95% CI: 51.6-70.6%). Only 2 patients with an undetectable prostate-specific antigen after radical retropubic prostatectomy biochemically relapsed (3%), compared to 47 relapses out of 61 patients (75%) who did not reach this level. Cox multivariate analysis confirms prostate-specific antigen nadir < or = 0.01 ng ml-1 to be a superb independent variable predicting a favourable biochemical disease-free survival (P < 0.0001). Early diagnosis of biochemical relapse is feasible with sensitive prostate-specific antigen assays. These assays more accurately measure the prostate-specific antigen nadir, which is an excellent predictor of biochemical disease-free survival. Thus, sensitive prostate-specific antigen assays offer accurate prognostic information and expedite decision-making regarding the use of salvage prostate-bed radiotherapy or hormone therapy.     

High-dose-rate intensity-modulated brachytherapy with external beam radiotherapy for prostate cancer: California endocurietherapy's 10-year results

PURPOSE: To present the long-term outcome and morbidity of high-dose-rate brachytherapy (HDR-BT) combined with external beam radiotherapy (EBRT) for localized prostate cancer. METHODS AND MATERIALS: Between September 1991 and December 1998, 209 consecutive patients with no prior androgen suppression were treated with HDR-BT plus EBRT. The median follow-up was 7.25 years (range, 5-12 years). The patients were stratified into three risk groups: low (Stage T2a or less, Gleason score 20). Four definitions of PSA progression were compared with the general clinical failure outcome: the American Society for Therapeutic Radiology and Oncology (ASTRO) definition, nadir plus 2.0 ng/mL, two consecutive rises >/=0.5 ng/mL, and PSA level >0.2 ng/mL. Morbidity was scored using Radiation Therapy Oncology Group criteria. RESULTS: The general clinical control rate was 90% (188 of 209), and the general clinical failure rate was 10% (21 of 209). The overall survival rate was 79%, and the cause-specific survival rate was 97%. The PSA progression-free survival (ASTRO definition) rate was 90%, 87%, and 69% for the low-, intermediate-, and high-risk groups, respectively. The nadir plus 2 ng/mL and two rises >/=0.5 definitions correlated better with the actual clinical outcome than did the ASTRO and PSA >0.2 ng/mL definitions. The rate of Grade 3 and 4 late urinary morbidity was 6.7% and 1%, respectively, mostly occurring in patients who had undergone post-RT transurethral prostate resection. No late Grade 3 or 4 rectal morbidity developed. The sexual potency preservation rate was 67%. CONCLUSION: Our 10-year results have demonstrated HDR-BT plus EBRT is a proven treatment for all stages of localized prostate cancer. The morbidity was low, but post-RT transurethral resection should be avoided.     

Stereotactic body radiotherapy for localized prostate cancer: Pooled analysis from a multi-institutional consortium of prospective phase II trials

Purpose

The effectiveness of stereotactic body radiotherapy (SBRT) for localized prostate cancer is tested.

Methods and materials

A total of 1100 patients with clinically localized prostate cancer were enrolled in separate prospective phase 2 clinical trials of SBRT from 8 institutions during 2003–11 and pooled for analysis. SBRT using the CyberKnife delivered a median dose of 36.25 Gy in 4–5 fractions. Patients were low-risk (58%), intermediate-risk (30%) and high-risk (11%). A short-course of androgen deprivation therapy (ADT) was given to 14%. PSA relapse defined as a rise >2 ng/ml above nadir was analyzed with the Kaplan Meier method.

Results

With a median follow-up of 36 months there were 49 patients with PSA failure (4.5%), 9 of whom were subsequently determined to be benign PSA bounces. The 5-year biochemical relapse free survival (bRFS) rate was 93% for all patients; 95%, 83% and 78% for GS ?6, 7 and ?8, respectively (p = 0.001), and 95%, 84% and 81% for low-, intermediate- and high-risk patients, respectively (p < 0.001). No differences were observed with ADT (p = 0.71) or as a function of total dose (p = 0.17). A PSA bounce of >0.2 ng/ml was noted among 16% of patients. For 135 patients possessing a minimum of 5 years follow-up, the 5-year bRFS rate for low- and intermediate-risk patients was 99% and 93%, respectively.

Conclusion

PSA relapse-free survival rates after SBRT compare favorably with other definitive treatments for low and intermediate risk patients. The current evidence supports consideration of SBRT among the therapeutic options for these patients.     

Dose-volume parameters of the corpora cavernosa do not correlate with erectile dysfunction after external beam radiotherapy for prostate cancer: results from a dose-escalation trial

PURPOSE: To analyze the correlation between dose-volume parameters of the corpora cavernosa and erectile dysfunction (ED) after external beam radiotherapy (EBRT) for prostate cancer. METHODS AND MATERIALS: Between June 1997 and February 2003, a randomized dose-escalation trial comparing 68 Gy and 78 Gy was conducted. Patients at our institute were asked to participate in an additional part of the trial evaluating sexual function. After exclusion of patients with less than 2 years of follow-up, ED at baseline, or treatment with hormonal therapy, 96 patients were eligible. The proximal corpora cavernosa (crura), the superiormost 1-cm segment of the crura, and the penile bulb were contoured on the planning computed tomography scan and dose-volume parameters were calculated. RESULTS: Two years after EBRT, 35 of the 96 patients had developed ED. No statistically significant correlations between ED 2 years after EBRT and dose-volume parameters of the crura, the superiormost 1-cm segment of the crura, or the penile bulb were found. The few patients using potency aids typically indicated to have ED. CONCLUSION: No correlation was found between ED after EBRT for prostate cancer and radiation dose to the crura or penile bulb. The present study is the largest study evaluating the correlation between ED and radiation dose to the corpora cavernosa after EBRT for prostate cancer. Until there is clear evidence that sparing the penile bulb or crura will reduce ED after EBRT, we advise to be careful in sparing these structures, especially when this involves reducing treatment margins.     

Secondary ovarian cancer after external beam radiotherapy for nonovarian pelvic malignancy

ObjectiveTo examine characteristics and survival of patients who developed secondary ovarian cancer after external beam radiotherapy (EBRT) for a prior nonovarian pelvic malignancy.MethodsThis is a population-based retrospective cohort study, querying the Surveillance, Epidemiology, and End Result program from 1975 to 2016. 167,269 women who received EBRT for 7 malignancies (anus, rectum, bladder, cervix, uterus, vulva, or vagina) were examined to identify subsequent secondary ovarian cancer diagnosis after EBRT. Then, within the ovarian cancer cohort (n = 147,618), characteristics and survival of patients with secondary ovarian cancer after EBRT were compared to those with ovarian cancer who did not receive prior EBRT.ResultsFollowing EBRT for a pelvic malignancy, 215 (1.3 per 1000) patients developed secondary ovarian cancer. Among those, the most frequent prior malignancy was cervical cancer (45.6%), followed by rectal cancer (20.9%). The median time from prior EBRT to secondary ovarian cancer was 8.8 years (interquartile range, 2.8–14.5). In multivariable analysis, patients with secondary ovarian cancer after EBRT were more likely to be older, and have a recent year of diagnosis, but less likely to have early-disease compared to ovarian cancer patients without prior EBRT (all, P < 0.05). In weighted model, patients with secondary ovarian cancer after EBRT had decreased overall survival compared to those with ovarian cancer without prior EBRT (5-year rates, 19.6% versus 39.9%, hazard ratio 1.62, 95% confidence interval 1.43–1.85). Similar association was observed in ages <70, ≥70, White, non-White, early-disease, and advanced-disease in sensitivity analyses.ConclusionRadiotherapy-related secondary ovarian cancer may be associated with decreased overall survival.     

Dose-response for biochemical control among high-risk prostate cancer patients after external beam radiotherapy

INTRODUCTION: The literature on dose-response characteristics of high-risk prostate cancer has been scarce in this era, when these patients are treated with hormone therapy along with radiotherapy. In this study, we estimated the dose-response of prostate-specific antigen (PSA) control probability in high-risk prostate cancer patients treated with radiotherapy alone. METHODS AND MATERIALS: The data set contains information on 363 high-risk prostate cancer patients who were treated with external beam radiotherapy without hormonal treatment between February 1987 and September 1998. These patients have one or more of the following adverse prognostic features: digital rectal examination stage > or =cT3, PSA >20 ng/mL, and biopsy Gleason score > or =8. These patients had biopsy-proven adenocarcinoma of prostate and were staged according to the 1992 AJCC staging system that was based on digital rectal examination. The logistic model was fitted to the data at various time points after treatment, and the dose-response parameters were estimated. RESULTS: The dose required to have 50% tumor control, TCD50 (95% confidence interval), for high-risk patients is 75.5 (range: 70.7-80.2) Gy. The gamma 50 (95% confidence interval) is 1.7 (range: 0.7-2.7) around 75.5 Gy. Recursive partitioning analysis based on the null Martingale residuals identifies two subgroups within the high-risk group. The TCD50 estimates of the two subgroups (PSA < or = vs. >20 ng/mL) differ by 15 Gy at 5 years. There is a dose response in both subgroups. CONCLUSION: We recognize that this study has the usual limitations of a retrospective study that includes treatment policy change that spanned a long time frame. However, our data strongly suggest a benefit of dose escalation for all the patients in the entire high-risk group. There is a steep dose response in PSA control probability around a modern dose of 78 Gy. A 5-Gy dose increase beyond 78 Gy may improve PSA control by about 10%.     

Variation in adherence to external beam radiotherapy quality measures among elderly men with localized prostate cancer

PURPOSE: To characterize the variation in adherence to quality measures of external beam radiotherapy (EBRT) for localized prostate cancer and its relation to patient and provider characteristics in a population-based, representative sample of U.S. men. METHODS AND MATERIALS: We evaluated EBRT quality measures proposed by a RAND expert panel of physicians among men aged >or=65 years diagnosed between 2000 and 2002 with localized prostate cancer and treated with primary EBRT using data from the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare program. We assessed the adherence to five EBRT quality measures that were amenable to analysis using SEER-Medicare data: (1) use of conformal RT planning; (2) use of high-energy (>10-MV) photons; (3) use of custom immobilization; (4) completion of two follow-up visits with a radiation oncologist in the year after therapy; and (5) radiation oncologist board certification. RESULTS: Of the 11,674 patients, 85% had received conformal RT planning, 75% had received high-energy photons, and 97% had received custom immobilization. One-third of patients had completed two follow-up visits with a radiation oncologist, although 91% had at least one visit with a urologist or radiation oncologist. Most patients (85%) had been treated by a board-certified radiation oncologist. CONCLUSIONS: The overall high adherence to EBRT quality measures masked substantial variation in geography, socioeconomic status in the area of residence, and teaching affiliation of the RT facility. Future research should examine the reasons for the variations in these measures and whether the variation is associated with important clinical outcomes.     

Prostate-specific antigen nadir within 12 months of prostate cancer radiotherapy predicts metastasis and death

BACKGROUND.The nadir prostate-specific antigen (PSA) at 1 year (nPSA12) was investigated as an early estimate of biochemical and clinical outcome after radiotherapy (RT) alone for localized prostate cancer.METHODS.From May 1989 to November 1999, 1000 men received 3D conformal RT alone (median, 76 Gy) with minimum and median follow-up periods of 26 and 58 months, respectively, from the end of treatment. The calculation of PSA doubling time (PSADT) was possible in 657 patients. Multivariate analyses (MVAs) via Cox proportional hazards regression were used to determine the association of nPSA12 to biochemical failure (BF; ASTRO definition), distant metastasis (DM), cause-specific mortality (CSM), and overall mortality (OM). Dichotomization of nPSA12 was optimized by evaluating the sequential model likelihood ratio and P-values.RESULTS.In MVA, nPSA12 as a continuous variable was independent of RT dose, T-stage, Gleason score, pretreatment initial PSA, age, and PSADT in predicting for BF, DM, CSM, and OM. Dichotomized nPSA12 (2 versus >2 ng/mL) was independently related to DM and CSM. Kaplan-Meier 10-year DM rates for nPSA12 2 versus >2 ng/mL were 4% versus 19% (P<.0001).CONCLUSIONS.nPSA12 is a strong independent predictor of outcome after RT alone for prostate cancer and should be useful in identifying patients at high risk for progression to metastasis and death.     

PSA kinetics after prostate brachytherapy: PSA bounce phenomenon and its implications for PSA doubling time

PURPOSE: To analyze prostate-specific antigen (PSA) kinetics in patients treated with prostate brachytherapy (PI) with a minimum of 5 years of PSA follow-up. METHODS AND MATERIALS: The records of 162 patients treated with PI for localized prostate cancer with a minimum of 5 years of PSA follow-up were reviewed. A variety of pretreatment and posttreatment variables were examined. Patients were coded as having a PSA bounce if their PSA achieved a nadir, elevated at least 0.2 ng/mL greater than that nadir, and decreased to, or below, the initial nadir. Two definitions of biochemical failure (bF) or biochemical relapse-free survival (bRFS) were used: the classic American Society for Therapeutic Radiology and Oncology consensus definition of three consecutive rises (bF3) and the nadir plus 2 ng/mL definition (bFn+2). Associations between a PSA bounce and the various pre- and posttreatment factors were assessed with logistic regression analysis, and the association between a PSA bounce and bF was examined with the log-rank test. The Mann-Whitney U test was applied to test for differences in the PSA doubling time (PSADT) and the time to a PSA rise between the PSA bounce patients and the bF patients. PSADT was calculated from the nadir to the time of the first PSA rise, because this point is known first in the clinical setting. RESULTS: The 5-year overall bRFS rate was 87% for the bF3 definition and 96% for the bFn+2 definition. A PSA bounce was experienced by 75 patients (46.3%). Patients who experienced a PSA bounce were less likely to have a bF, regardless of the bRFS definition used (bF3: p=0.0015; bFn+2: p=0.0040). Among the pre- and posttreatment factors, only younger age predicted for a PSA bounce on multivariate analysis (p=0.0018). The use of androgen deprivation had no effect on PSA bounce. No difference was found in the PSADT between patients who had a PSA bounce and those with bF. The median PSADT for those with a PSA bounce was 8.3 months vs. 10.3 months using the bF3 definition and 8.8 months using the bFn+2 definition. However, a significant difference was found in the time to the first rise in PSA after PI for patients with a PSA bounce vs. patients with bF. The median time to the first rise in PSA after nadir for those with a PSA bounce was 15.1 months vs. 30.0 months using the bF3 definition (p=0.001) and 22.3 months using the bFn+2 definition (p=0.013). CONCLUSION: Patients experiencing a PSA bounce are more likely to be younger and will have a better bRFS. The PSADT cannot differentiate a PSA bounce from bF. The time to the initial PSA rise after nadir is an excellent discriminator of bF from PSA bounce. The time of the PSA rise after nadir occurs far sooner for a PSA bounce than for bF. This factor should be considered when assessing a patient with a rising PSA level after PI before a patient is administered salvage therapy.     

A multi-institutional analysis comparing adjuvant and salvage radiation therapy for high-risk prostate cancer patients with undetectable PSA after prostatectomy

Background and purpose

In men with adverse pathology at the time of radical prostatectomy (RP), the most appropriate timing to administer radiotherapy (RT) remains a subject for debate. To determine whether salvage radiotherapy (SRT) upon early prostate-specific antigen (PSA) relapse is equivalent to immediate adjuvant radiotherapy (ART) post RP.

Material and methods

130 patients receiving ART and 89 receiving SRT were identified. All had an undetectable PSA after RP. Homogeneous subgroups were built based on the status (±) of lymphatic invasion (LVI) and surgical margins (SM), to allow a comparison of ART and SRT. Biochemical disease-free survival (bDFS) was calculated from the date of surgery and from the end of RT. The multivariate analysis was performed using the Cox Proportional hazard model.

Results

In the SM−/LVI− and SM+/LVI− groups, SRT was a significant predictor of a decreased bDFS from the date of surgery, while in the SM+/LVI+ group, there was a trend towards significance. From the end of RT, SRT was also a significant predictor of a decreased bDFS in three patient groups: SM−/LVI−, SM+/LVI− and SM+/LVI+. Gleason score >7 showed to be another factor on multivariate analysis associated with decreased bDFS in the SM−/LVI− group, from the date of surgery and end of RT. Preoperative PSA was a significant predictor in the SM−/LVI− group from the date of RP only.

Conclusions

Immediate ART post RP for patients with high risk features in the prostatectomy specimen significantly reduces bDFS after RP compared with early SRT upon PSA relapse.     

MRI before and after external beam intensity-modulated radiotherapy of patients with prostate cancer: The feasibility of monitoring of radiation-induced tissue changes using a dynamic contrast-enhanced inversion-prepared dual-contrast gradient echo sequence

Purpose

To identify and quantify suitable pharmacokinetic MRI parameters for monitoring tissue changes after external beam intensity-modulated radiotherapy of prostate cancer.

Material and methods

Six patients with biopsy-proven prostate cancer (initial PSA, 6.0-81.4 ng/ml) underwent MRI at 1.5 T using a combined endorectal/body phased-array coil and a dynamic contrast-enhanced inversion-prepared dual-contrast gradient echo sequence (T1/T2^∗w; 1.65 s temporal resolution). MRI was performed before and immediately after radiotherapy, at 3 months and at 1 year. Perfusion, blood volume, mean transit time, delay, dispersion, interstitial volume, and extraction coefficient were calculated in prostate cancer and normal prostate for all four time points using a sequential 3-compartment model.

Results

Prostate cancer and normal prostate tissue showed a statistically significant decrease in perfusion (p = 0.006, p = 0.001) and increase in extraction coefficient (p = 0.004, p < 0.001). For prostate cancer, there was also a decrease in vascular volume (p = 0.034). The other parameters investigated showed no statistically significant changes. Statistically significant differences between prostate cancer and normal prostate tissue were only observed before radiotherapy, when prostate cancer showed significantly higher perfusion (1.84 vs. 0.12 ml/cm³ min, p = 0.028) and a smaller extraction coefficient (0.42 vs. 0.64, p = 0.028).

Conclusions

Two pharmacokinetic parameters, perfusion and extraction coefficient, appear to be suitable candidates for monitoring the response to percutaneous intensity-modulated radiotherapy of prostate cancer.     

Prognostic value of biochemical response to neoadjuvant androgen deprivation before external beam radiotherapy for prostate cancer: A systematic review of the literature

External beam radiation therapy (EBRT) in combination with androgen deprivation therapy (ADT) is considered a standard treatment option for patients with aggressive localized and locally-advanced prostate cancer. Randomized phase III trials have provided evidence for combining EBRT to short-term ADT for intermediate-risk disease and to long-term ADT for patients harboring high-risk tumors. Even if several improvements and developments have been made in the last years in terms of radiotherapy delivery techniques, image-guided radiotherapy, and better sparing of the organs at risk the current use of ADT remains still linked to a therapeutic algorithm based on the prostate cancer risk classification as proposed by clinical trials.Emerging literature has recently shown that the biochemical response to a course of neoadjuvant ADT before EBRT, called the “prostate-specific antigen (PSA) nadir” (lowest value after treatment), may influence the long-term biochemical tumor-control outcomes of prostate cancer patients. An individualized approach adapting the duration of hormonal treatment according to the PSA response during the neoadjuvant phase, as well using new generation hormonal agents, may represent a new therapeutic strategy and a future way to improve the therapeutic ratio for prostate cancer patients.In this systematic review of the literature we explored the prognostic value of the PSA response to the neoadjuvant ADT phase and the rationale to adjust the use of ADT and EBRT in patients with intermediate- and high-risk prostate cancer based on the biochemical response to the neoadjuvant androgen ablation phase.     

First-year PSA kinetics and minima after prostate cancer radiotherapy are predictive of overall survival

PURPOSE: We analyzed whether first-year prostate-specific antigen (PSA) kinetics and minima are predictive of overall survival (OS). METHODS AND MATERIALS: The data set contained 1,174 patients treated with external beam radiotherapy (RT) from 1987 to 2001. The relative rate of change (lambda) in post-RT PSA values during the first year (13.5 months) was computed using regression analysis of ln(PSA) vs. time. We also computed the PSA minimum (mPSA) reached during the same period. Recursive partitioning analysis was used to identify the relevant cutpoints for the factors being investigated for its association with survival: age, pretreatment PSA, radiation dose, relative rate of change in PSA post-RT, and 1-year PSA minimum. For each of the other factors stage, Gleason score and risk group, all possible cutpoints were considered in the multivariate analyses. Significant factors were considered in the multivariate analyses to identify independent predictors for overall survival. RESULTS: The median value of lambda was -1.0 years(-1) (range, -11.0-5.1 years(-1)). The 1-year minimum had a median of 0.8 ng/mL (range, 0.01-30.9 ng/mL). Recursive partitioning analysis and Cox proportional hazards analyses identified the following pretreatment or treatment factors adversely related to OS: age, Gleason score, stage, and dose. First-year mPSA > or = 4 ng/mL and lambda > 0 were post-RT independent prognostic factors for worse OS. CONCLUSION: First-year post-RT PSA kinetics and minima are early response parameters predictive of overall survival for prostate cancer patients. These factors may be useful in selecting patients for early salvage therapy.