Defining biochemical recurrence after radical prostatectomy and timing of early salvage radiotherapy

Background

The optimal prostate-specific antigen (PSA) level after radical prostatectomy (RP) for defining biochemical recurrence and initiating salvage radiation therapy (SRT) is still debatable. Whereas adjuvant or extremely early SRT irrespective of PSA progression might be overtreatment for some patients, SRT at PSA >0.2?ng/ml might be undertreatment for others. The current study addresses the optimal timing of radiation therapy after RP.

Patients and methods

Cohort 1 comprised 293 men with PSA 0.1–0.19?ng/ml after RP. Cohort 2 comprised 198 men with SRT. PSA progression and metastases were assessed in cohort 1. In cohort 2, we compared freedom from progression according to pre-SRT PSA (0.03–0.19 vs. 0.2–0.499?ng/ml). Multivariable Cox regression analyses predicted progression after SRT.

Results

In cohort 1, 281 (95.9%) men had further PSA progression ≥0.2?ng/ml and 27 (9.2%) men developed metastases within a median follow-up of 74.3 months. In cohort 2, we recorded improved freedom from progression according to lower pre-SRT PSA (0.03–0.19 vs. 0.2–0.499?ng/ml: 69 vs. 53%; log-rank p = 0.051). Patients with higher pre-SRT PSA ≥0.2?ng/ml were at a higher risk of progression after SRT (hazard ratio: 1.8; p < 0.05).

Conclusion

The vast majority of patients with PSA ≥0.1?ng/ml after RP will progress to PSA ≥0.2?ng/ml. Additionally, early administration of SRT at post-RP PSA level <0.2?ng/ml might improve freedom from progression. Consequently, we suggest a PSA threshold of 0.1?ng/ml to define biochemical recurrence after RP.

     

Three linked nomograms for predicting biochemical failure in prostate cancer treated with radiotherapy plus androgen deprivation therapy

Background

Nomograms were established to predict biochemical recurrence (BCR) after radiotherapy (RT) with a low weight of the characteristic variables of RT and androgen deprivation therapy (ADT). Our aim is to provide a new stratified tool for predicting BCR at 4 and 7 years in patients treated using RT with radical intent.

Materials and methods

A retrospective, nonrandomized analysis was performed on 5044 prostate cancer (PCa) patients with median age 70 years, who received RT—with or without ADT—between November 1992 and May 2007. Median follow-up was 5.5 years. BCR was defined as a rise in serum prostate-specific antigen (PSA) of 2 ng/ml over the post-treatment PSA nadir. Univariate association between predictor variables and BCR was assessed by the log-rank test, and three linked nomograms were created for multivariate prognosis of BCR-free survival. Each nomogram corresponds to a category of the Gleason score—either 6,7, or 8–10—and all of them were created from a single proportional hazards regression model stratified also by months of ADT (0, 1–6, 7–12, 13–24, 25–36, 36–60). The performance of this model was analyzed by calibration, discrimination, and clinical utility.

Results

Initial PSA, clinical stage, and RT dose were significant variables (p?<?0.01). The model showed a good calibration. The concordance probability was 0.779, improving those obtained with other nomograms (0.587, 0.571, 0.554) in the database. Survival curves showed best clinical utility in a comparison with National Comprehensive Cancer Network (NCCN) risk groups.

Conclusion

For each Gleason score category, the nomogram provides information on the benefit of adding ADT to a specific RT dose.

     

The impact of androgen deprivation therapy on setup errors during external beam radiation therapy for prostate cancer

Purpose

To determine whether setup errors during external beam radiation therapy (RT) for prostate cancer are influenced by the combination of androgen deprivation treatment (ADT) and RT.

Materials and methods

Data from 175 patients treated for prostate cancer were retrospectively analyzed. Treatment was as follows: concurrent ADT plus RT, 33 patients (19%); neoadjuvant and concurrent ADT plus RT, 91 patients (52%); RT only, 51 patients (29%). Required couch shifts without rotations were recorded for each megavoltage (MV) cone beam computed tomography (CBCT) scan, and corresponding alignment shifts were recorded as left–right (x), superior–inferior (y), and anterior–posterior (z). The nonparametric Mann–Whitney test was used to compare shifts by group. Pearson’s correlation coefficient was used to measure the correlation of couch shifts between groups. Mean prostate shifts and standard deviations (SD) were calculated and pooled to obtain mean or group systematic error (M), SD of systematic error (Σ), and SD of random error (σ).

Results

No significant differences were observed in prostate shifts in any direction between the groups. Shifts on CBCT were all less than setup margins. A significant positive correlation was observed between prostate volume and the z?direction prostate shift (r = 0.19, p = 0.04), regardless of ADT group, but not between volume and x? or y?direction shifts (r = 0.04, p = 0.7; r = 0.03, p = 0.7). Random and systematic errors for all patient cohorts and ADT groups were similar.

Conclusion

Hormone therapy given concurrently with RT was not found to significantly impact setup errors. Prostate volume was significantly correlated with shifts in the anterior–posterior direction only.

     

Salvage radiotherapy in prostate cancer patients with biochemical relapse after radical prostatectomy

Background

In patients with prostate cancer (PCa) and biochemical progression (BP) after radical prostatectomy (RP), salvage radiotherapy (sRT) improves prostate cancer-specific survival (PCSS), but this evidence is based only on retrospective data.

Patients and methods

In addition to our previous study of 151 patients with PCa and BP after RP, we performed univariate analyses of prostate-specific antigen (PSA) kinetics during sRT. In 11 patients with BP or initiation of hormonal treatment (HT) within 180 days after sRT, risk factors were assessed using Mann–Whitney U tests. PSA doubling times (PSADT) before and after sRT in 82 patients with BP after sRT were compared by a Wilcoxon test.

Results

After a median follow-up of 82 months, analysis of PSA kinetics during sRT did not show a statistically significant impact on a subsequent BP, PCSS, or overall survival at an administered dose of 30 or 45?Gy. The subgroup analysis of patients with early BP or early HT revealed higher Gleason scores (p = 0.008) and preoperative PSA values (p = 0.005), shorter PSADT prior to sRT (p < 0.0005), and longer time intervals from RP until the start of sRT (p = 0.005) compared to all other patients. In patients with subsequent BP, PSADTs were significantly prolonged after sRT (median PSADT 4.5 months before and 9.9 months after sRT, p < 0.0005).

Conclusion

PSA monitoring during sRT did not predict the therapeutic success. Subgroup analysis suggests a lower probability of benefit for patients with the abovenamed risk factors . However, the prolonged PSADT after sRT reflects a benefit of sRT for the vast majority of patients.

     

High-dose-rate interstitial brachytherapy in combination with androgen deprivation therapy for prostate cancer

Background and purpose

To evaluate the effectiveness of high-dose-rate interstitial brachytherapy (HDR-ISBT) as the only form of radiotherapy for high-risk prostate cancer patients.

Patients and methods

Between July 2003 and June 2008, we retrospectively evaluated the outcomes of 48 high-risk patients who had undergone HDR-ISBT at the National Hospital Organization Osaka National Hospital. Risk group classification was according to the criteria described in the National Comprehensive Cancer Network (NCCN) guidelines. Median follow-up was 73 months (range 12–109 months). Neoadjuvant androgen deprivation therapy (ADT) was administered to all 48 patients; 12 patients also received adjuvant ADT. Maximal androgen blockade was performed in 37 patients. Median total treatment duration was 8 months (range 3–45 months). The planned prescribed dose was 54 Gy in 9 fractions over 5 days for the first 13 patients and 49 Gy in 7 fractions over 4 days for 34 patients. Only one patient who was over 80 years old received 38 Gy in 4 fractions over 3 days. The clinical target volume (CTV) was calculated for the prostate gland and the medial side of the seminal vesicles. A 10-mm cranial margin was added to the CTV to create the planning target volume (PTV).

Results

The 5-year overall survival and biochemical control rates were 98 and 87?%, respectively. Grade 3 late genitourinary and gastrointestinal complications occurred in 2 patients (4?%) and 1 patient (2?%), respectively; grade 2 late genitourinary and gastrointestinal complications occurred in 5  patients (10?%) and 1 patient (2?%), respectively.

Conclusion

Even for high-risk patients, HDR-ISBT as the only form of radiotherapy combined with ADT achieved promising biochemical control results, with acceptable late genitourinary and gastrointestinal complication rates.     

Salvage radiotherapy in patients with prostate cancer and biochemical relapse after radical prostatectomy

Background and purpose

In patients with prostate cancer (PC) and biochemical relapse after radical prostatectomy, salvage radiotherapy (SRT) could improve PC-specific survival (PCSS) but the timing for initiation is still under discussion. We have demonstrated a low rate of biochemical relapses in a patient series with very low pre-SRT PSA levels after a median follow-up of 42 months. Here, we present an update of that study.

Patients and methods

Overall, 151 patients were analyzed. A biochemical relapse after SRT was diagnosed when the PSA exceeded the post-SRT nadir by 0.2 ng/ml with subsequent increase. Parameters with significant impact on biochemical progression-free survival (BPFS), PCSS, and overall survival (OS) in univariate analysis were included in a multiple Cox regression analysis.

Results

After a median follow-up of 82 months, 18 patients (12?%) had died with 10 (6.6?%) deaths being PC-related. A biochemical progression was diagnosed in 83 patients (55?%). Univariate analysis revealed a significant impact of pre-SRT PSA level, Gleason score, and PSA doubling time (PSADT) on BPFS and for initial tumor stage and Gleason score on OS. Multivariate analysis confirmed the impact of pre-SRT PSA level, Gleason score, and PSADT on BPFS and tumor stage on OS.

Conclusion

In this update, the rate of biochemical relapses increased compared with our previous data. Compared to similar studies, we found a remarkably low rate of PC-related deaths. Our data support early initiation of SRT. However, this treatment strategy, triggered by very low PSA levels, could carry the risk of overtreatment in at least a subset of patients.     

68Ga-PSMA-11 PET imaging in patients with ongoing androgen deprivation therapy for advanced prostate cancer

Annals of Nuclear Medicine - Prostate-specific membrane antigen (PSMA) targeted positron emission tomography (PET) imaging significantly improved the detection of recurrent prostate cancer (PCa)....     

Factors impacting all-cause mortality in prostate cancer brachytherapy patients with or without androgen deprivation therapy

PurposeCertain subsets of patients have an increased risk of all-cause mortality when androgen deprivation therapy (ADT) is used with definitive radiotherapy. We evaluated the relationship between pretreatment serum testosterone, age, and comorbidities on survival after prostate brachytherapy in men treated with and without ADT.Methods and MaterialsFrom October 2001 to September 2005, 803 patients underwent brachytherapy and 720 had a pretreatment serum testosterone. Comorbidities were prospectively recorded for each patient (body mass index > 30, hypertension, diabetes, current smoker). Median followup was 5.0 years. 34.2% of the patients received ADT. Focus was on subset of men who might be expected to have more significant side effects associated with ADT.ResultsADT did not significantly impact overall survival (OS) in men <65 years, >65 years, with one or no comorbidities, with more than one comorbidity, or with normal/high testosterone level. ADT use in men with low testosterone level was associated with decreased OS (83.6% vs. 93.1%, p = 0.01). The adverse impact of ADT in men with low testosterone level was restricted to men with low testosterone level and more than one comorbidity (OS of 71.3% vs. 92.8%, p < 0.01), with death from cardiovascular diseases accounting for almost all of the excess mortality. The subset of men with multiple comorbidities and normal/high testosterone level did not experience adverse OS with ADT.ConclusionsLow pretreatment testosterone level may be a marker for men at increased risk of premature death with ADT. The combination of low pretreatment serum testosterone level and multiple preexisting comorbidities is associated with decreased OS when ADT is incorporated into treatment.     

Adjuvant and salvage radiation therapy after prostatectomy: investigating beliefs and practices of radiation oncologists

Objective:

Evidence regarding adjuvant radiation therapy (ART) and salvage radiation therapy (SRT) following radical prostatectomy (RP) for prostate cancer is inconsistent. The study objectives were to collect survey information on Italian radiation oncologists'' (RO) beliefs regarding the use of ART and SRT following RP and to compare the results of Italian RO with those of American RO available from an analogous survey.

Methods:

A modified version of a US-based questionnaire captured attitudes and clinical approaches regarding post-RP RT of all 716 RO practicing in 147 radiation oncology centres in Italy. Bivariate analyses compared the responses of Italian RO with those of American RO retrieved from a previously published study.

Results:

Analysable questionnaires were completed by 153 Italian RO (response rate, 21%). Variations in practice were found for RT use, timing, dosage and technique. All Italian RO supported ART use, although factors influencing the decision to initiate ART varied. Most RO (81%) would wait 3–6 months after surgery before beginning RT. Compared with Italian RO, more American RO believed ART improves survival outcomes (70% vs 35%, p < 0.001), would initiate ART based solely on adverse pathological features (79% vs 69%, p < 0.001) and would initiate SRT based on any detectable prostate-specific antigen (37% vs 11%, p < 0.001).

Conclusion:

Italian RO strongly supported ART, but their approach to patient selection for ART and SRT varied. Striking differences between Italian RO and American RO regarding ART and SRT practices were found.

Advance in knowledge

Differential RT practices and perceptions exist among RO internationally. Clinical studies must inform evidence-based guidelines to harmonize the use of post-RP RT.     

Outcomes of salvage high dose-rate brachytherapy with or without pelvic external beam radiotherapy in patients with palpable local recurrence of prostate cancer after radical prostatectomy

PurposeThis study aims to evaluate the outcomes and toxicities in patients with palpable local recurrence of prostate cancer after radical prostatectomy (RP), who were treated with salvage high dose-rate brachytherapy (HDR-BT) with or without pelvic external beam radiotherapy (EBRT).MethodsThis retrospective review included patients with palpable local recurrence of prostate cancer after RP who underwent salvage HDR-BT at a single institution between 2002 and 2020. HDR-BT regimens included 950 cGy x 2 (N = 4) or 1500 cGy x 1 (N = 2) combined with EBRT; or monotherapy with 950 cGy x 4 (N = 1) or 800 cGy x 2 (N = 1). Toxicity was graded according to CTCAE Version 5.0.ResultsA total of 8 patients were included. Median follow-up was 49 months (range: 9–223 months). Median age at time of salvage brachytherapy was 68 years (range: 59–85 years). Seven out of 8 patients were alive at last follow-up. There have been no locoregional recurrences. Three patients developed distant metastatic disease. One patient developed acute grade 3 urinary obstruction requiring catheterization, which lasted for 1 day postbrachytherapy. One patient developed late grade 3 urinary incontinence 18 months after brachytherapy. There were no other grade 2+ toxicities.ConclusionsThis study demonstrates the safety and efficacy of salvage HDR-BT in the setting of palpable local recurrence of prostate cancer after RP, with durable locoregional control and acceptable rates of toxicity. HDR-BT should be further explored as an option for dose-escalated salvage radiotherapy after prior radical prostatectomy.     

Distant and local recurrence in patients with biochemical failure after prostate brachytherapy

PURPOSE: To analyze the patterns of failure after the brachytherapy management of localized prostate cancer. METHODS AND MATERIALS: From 1990 to 2008, 2869 patients underwent prostate brachytherapy and 213 experienced a prostate-specific antigen (PSA) failure by the Phoenix definition. Of these 213 patients, 33.5% were low, 18.5% intermediate, and 58% high risk. RESULTS: Of the 119 patients biopsied, 36 (30%) had a least one positive posttreatment biopsy. In univariate and multivariate analyses, PSA doubling time was the most predictive of a positive biopsy. Patients with doubling times < or =3, >3-6, > or =6-10, and >10 months had positive biopsy rates of 9%, 18%, 36%, and 42%, respectively (p=0.01). The actuarial rate of remaining free from distant metastases at 10 years was 73%. Patients with PSA doubling times of < or =3, >3-6, >6-10, and >10 months had freedom from distant metastases rates of 0%, 74%, 78%, and 94.5% at 10 years, respectively (p<0.0001). In multivariate analysis, PSA doubling time and time to PSA failure were the most significant predictors of developing distant metastases. CONCLUSIONS: About one third of patients harbor a component of local failure and one fourth demonstrate clinical metastases. PSA doubling time can be used to help predict the source of a rising PSA.     

Impact of long-term androgen deprivation therapy on PSMA ligand PET/CT in patients with castration-sensitive prostate cancer

Purpose

Since the introduction of PSMA PET/CT with ⁶⁸Ga-PSMA-11, this modality for imaging prostate cancer (PC) has spread worldwide. Preclinical studies have demonstrated that short-term androgen deprivation therapy (ADT) can significantly increase PSMA expression on PC cells. Additionally, retrospective clinical data in large patient cohorts suggest a positive association between ongoing ADT and a pathological PSMA PET/CT scan. The present evaluation was conducted to further analyse the influence of long-term ADT on PSMA PET/CT findings.

Methods

A retrospective analysis was performed of all 1,704 patients who underwent a ⁶⁸Ga-PSMA-11 PET/CT scan at our institution from 2011 to 2017 to detect PC. Of 306 patients scanned at least twice, 10 had started and continued ADT with a continuous clinical response between the two PSMA PET/CT scans. These ten patients were included in the current analysis which compared the tracer uptake intensity and volume of PC lesions on PSMA PET/CT before and during ongoing ADT.

Results

Overall, 31 PC lesions were visible in all ten patients before initiation of ADT. However, during ongoing ADT (duration 42–369 days, median 230 days), only 14 lesions were visible in eight of the ten patients. The average tracer uptake values decreased in 71% and increased in 12.9% of the PC lesions. Of all lesions, 33.3% were still visible in six patients with a complete PSA response (≤0.1 ng/ml).

Conclusion

Continuous long-term ADT significantly reduces the visibility of castration-sensitive PC on PSMA PET/CT. If the objective is visualization of the maximum possible extent of disease, we recommend referring patients for PSMA PET/CT before starting ADT.

     

Effects of strength training on muscle cellular outcomes in prostate cancer patients on androgen deprivation therapy

Androgen deprivation therapy (ADT) improves life expectancy in prostate cancer (PCa) patients, but is associated with adverse effects on muscle mass. Here, we investigated the effects of strength training during ADT on muscle fiber cross‐sectional area (CSA) and regulators of muscle mass. PCa patients on ADT were randomized to 16 weeks of strength training (STG) (n = 12) or a control group (CG; n = 11). Muscle biopsies were obtained from m. vastus lateralis and analyzed by immunohistochemistry and western blot. Muscle fiber CSA increased with strength training (898 μm², P = 0.04), with the only significant increase observed in type II fibers (1076 μm², P = 0.03). There was a trend toward a difference in mean change between groups myonuclei number (0.33 nuclei/fiber, P = 0.06), with the only significant increase observed in type I fibers, which decreased the myonuclear domain size of type I fibers (P = 0.05). Satellite cell numbers and the content of androgen receptor and myostatin remained unchanged. Sixteen weeks of strength training during ADT increased type II fiber CSA and reduced myonuclear domain in type I fibers in PCa patients. The increased number of satellite cells normally seen following strength training was not observed.     

The effect of androgen deprivation therapy on 68 Ga-PSMA tracer uptake in non-metastatic prostate cancer patients

To evaluate the effect of neoadjuvant androgen deprivation treatment (ADT) on prostate-specific membrane antigen (PSMA) tracer uptake demonstrated in 68Ga-PSMA-positron emission tomography (PET/CT) in non-metastatic hormone-naïve prostate cancer (PC) patients. The clinical data of 108 PC patients who received neoadjuvant ADT were retrospectively analyzed. All patients had a baseline 68Ga-PSMA-PET/CT scan, and a second scan was delivered median of 2.9 months after the initiation of ADT. The maximum standardized uptake value (SUVmax) of primary tumor (SUVp) and metastatic lymph nodes (SUVln) as well as PSA response were assessed between pre- and post-ADT 68Ga-PSMA-PET/CT scans. There were significant decreases in posttreatment serum PSA, SUVp, and SUVln. A decrease in SUVp was seen in 91 patients (84%) with a median value of 66% (range, 5–100%), while 17 patients (16%) had no change in or an increase in PSMA tracer uptake with a median value of 24% (range, 0–198%). Patients with Gleason score (GS) of 7 had significantly higher metabolic response rates compared to other patients. The disease progression was significantly higher only in patients with GS > 7 disease compared to GS 7 disease. The PSA response to ADT was the lowest in patients with ISUP high-grade tumors. A total of 16 patients (15%) had progressive disease, and in 9 patients (8%), radiotherapy decisions were modified according to posttreatment 68Ga-PSMA-PET/CT scans. The current study includes the largest number of patients analyzed to date and demonstrates that ADT causes a significant decrease in serum PSA values and SUVp and SUVln. The authors demonstrate that 68Ga-PSMA-PET/CT may be used as a quantitative imaging modality after neoadjuvant ADT in hormone-naïve non-metastatic PC patients.     

中等大分割调强放疗联合内分泌治疗局部晚期前列腺癌的疗效分析

目的探讨中等大分割调强放疗(IMRT)联合内分泌治疗局部晚期前列腺癌的疗效和不良反应。方法回顾性选取大连医科大学附属第二医院肿瘤放疗科2014至2020年收治的40例局部晚期前列腺腺癌患者的病例资料。前列腺及精囊腺计划肿瘤靶区(PGTV)剂量:64.8～70.0 Gy/25～28次, 2.4～2.8 Gy/次, 其中, 20例盆腔阳性淋巴结同步加量PGTVnd剂量:60.0～64.4 Gy/25～28次, 2.3～2.4Gy/次。盆腔淋巴结引流区计划靶区(PTV)剂量为45.0～50.4 Gy/25～28次。入组患者采用长程内分泌治疗, 包括新辅助、同期及辅助治疗。评价疗效及不良反应, 并分析影响无生化失败生存(BFFS)的预后相关因素。结果中位随访时间为31个月, 全组患者2、3年的总生存(OS)率分别为100.0%、96.9%, 1 、2 、3年的BFFS率分别为90%、76.8%、72%, 无远处转移生存(DMFS)率分别为92.2%、82.8%、75.1%。Gleason(GS)评分高低(χ2=10.00, P<0.05)和有无邻近组织受侵(χ2=8.85, P<0...     

High-dose-rate brachytherapy with or without intensity modulated radiation therapy as salvage treatment for an isolated,gross local recurrence of prostate cancer post-prostatectomy

PurposeTo evaluate the use of high-dose-rate (HDR) brachytherapy ± intensity modulated radiation therapy (IMRT) as salvage therapy for patients with an isolated, gross local recurrence of prostate cancer after radical prostatectomy.Methods and MaterialsBetween October 2009 and May 2013, the authors treated six patients with salvage iridium-192 HDR brachytherapy ± IMRT for biopsy-proven, recurrent prostate cancer post-prostatectomy. In each patient, a pelvic MRI scan or CT scan demonstrated a nodule (range 1.6, 4.7 cm) in the prostate bed. Although prostate-specific antigen values were 0.2–9.5 ng/mL at the time of salvage brachytherapy, there was no pelvic adenopathy on CT or MRI scan, and a bone scan was negative in all cases. Five patients were treated with IMRT to 4500–5040 cGy in 25–28 fractions to the prostate bed followed by two 950 cGy HDR brachytherapy fractions separated by 1–2 weeks. A sixth patient underwent HDR brachytherapy monotherapy consisting of 3800 cGy in four fractions over 3 days. Toxicities were graded according to the Common Terminology Criteria for Adverse Events, version 4.0.ResultsMedian followup was 9 months (range 3, 40 months). All six patients have been free of androgen deprivation therapy and have an undetectable prostate-specific antigen. One patient developed late Grade 2 urinary incontinence. There was no late grade ≥2 gastrointestinal toxicity.ConclusionsHDR brachytherapy ± IMRT is a safe and effective salvage therapy option for an isolated, gross local recurrence of prostate cancer after radical prostatectomy and merits further study.