Postoperative radiotherapy in prostate cancer: Analysis of prognostic factors in a series of 282 patients

Aim

To assess the outcomes of patients treated with postoperative RT in relation to the possible prognostic factors.

Background

Postoperative radiotherapy (RT) has been proved to reduce the risk of biochemical recurrence in high-risk prostate cancer patients. Baseline prostate specific antigen (PSA), pathological Gleason score (GS), positive surgical margins, nodal status and seminal vesicle invasion are independent predictors of biochemical relapse.

Materials and methods

The clinical records of 282 patients who underwent postoperative RT were retrospectively reviewed. The prognostic value of postoperative PSA, preoperative risk class, nodal status, pathological GS, margins status, and administration of hormonal therapy (HT) was analyzed.

Results

Postoperative RT was delivered with a median dose to the prostatic fossa of 66 Gy (range 50–72) in 1.8–2 Gy/fraction. Median follow-up was 23.1 months (range 6–119). Five-year actuarial biochemical disease-free survival (bDFS) and overall survival rates were 76% and 95%, respectively. Higher bDFS was found for patients with postoperative PSA <0.02 ng/ml (p = 0.03), low preoperative risk class (p = 0.01), pN0 (p = 0.003), GS 4–6 (p = 0.0006), no androgen deprivation therapy (p = 0.02), and irrespective of surgical margin status (p = 0.10). Multivariate analysis showed that postoperative PSA and Gleason score had a significant impact on bDFS (p = 0.039 and p = 0.05, respectively).

Conclusions

Postoperative RT with a dose of 66 Gy offers an acceptable toxicity and an optimal disease control after radical prostatectomy in patients with different risk features. A postoperative PSA >0.02 ng/ml could be considered as a prognostic factor and a tool to select patients at risk for progression.     

68Ga-PSMA-HBED-CC PET/MRI is superior to multiparametric magnetic resonance imaging in men with biochemical recurrent prostate cancer: A prospective single-institutional study

BackgroundThe primary objective was to compare the overall diagnostic performance, presented as detection rate of ⁶⁸Ga-PSMA-HBED-CC positron emission tomography/magnetic resonance imaging (PSMA PET/MRI) versus conventional, multiparametric MRI (mpMRI) in a population of patients with biochemically recurrent prostate cancer. In conjunction with this analysis, secondary objectives included the evaluation of the detection rate stratified by PSA levels and primary treatment modality.MethodsA total of 165 PSMA PET MRI were performed from April 2018 to May 2021, of whom 108 were presenting for biochemical recurrent disease. The PSMA PET vertex to thigh were read by two different board-certified nuclear medicine physicians while the MRI head and neck, chest, abdomen, and pelvis (with dedicated, PI-RADS compliant multiparametric prostate MRI) were read by two board certified diagnostic radiologists.AnalysisPSMA PET/MRI had a higher detection rate than mpMRI when evaluating patients with biochemical recurrence (BCR) with similar results demonstrated when sub-analysis was performed using PSA levels, primary treatment modality, and time since androgen deprivation therapy. Our study also showed PSMA PET/MRI had a higher sensitivity than mpMRI.DiscussionOur findings demonstrate that PSMA PET/MRI is a better imaging modality in the detection of disease in the setting of BCR when compared to MRI alone. Combined utility with PSMA PET/MRI is a powerful tool which can aid in not only the detection of disease, but also guide in treatment planning for prostate cancer patients.     

Salvage I-125 brachytherapy for locally-recurrent prostate cancer after radiotherapy

PurposeRetrospective, single-institution analysis of clinical outcomes and treatment-related toxicity in patients treated with salvage I-125 low-dose rate (LDR) brachytherapy (BT) for locally-recurrent prostate cancer after radiotherapy.Materials and methodsBetween 2008 and 2018, 30 patients with biopsy-confirmed prostate cancer recurrence underwent salvage treatment with I-125 LDR-BT. Of these 30 patients, 14 were previously treated with primary external beam radiotherapy (EBRT; median dose, 73 Gy) and 16 with primary I-125 LDR-BT (145 Gy and 160 Gy in 14 and 2 cases, respectively). At seed implantation, the mean age was 75.8 years, with a median Gleason score of 7 and pre-salvage PSA of <10 ng/mL. Six patients received androgen deprivation therapy for six months after relapse diagnosis. The prescribed salvage I-125 BT dose to the gland was 120−130 Gy, with dose restrictions of Dmax <135% (urethra) and <100% (rectum). Toxicity was evaluated according to the CTCAE scale (v4.0).ResultsAt a median follow-up of 45 months, the biochemical recurrence-free survival rates at 1, 3 and 5 years were 86.7%, 56.7% and 53.3%, respectively. Overall survival at 5 years was 87%. On the multivariate analysis, two variables were significant predictors of recurrence: PSA at relapse and nadir PSA post-salvage. Grade 3 genitourinary toxicity was observed in 5 patients (radiation-induced cystitis in 3 cases and urethral stenosis in 2) and G3 gastrointestinal toxicity in 3 patients (rectal bleeding).ConclusionSalvage therapy with I-125 brachytherapy is a safe and effective treatment option for locally-recurrent prostate cancer in previously-irradiated patients. High pre-salvage PSA and post-salvage nadir PSA values were significantly associated with a worse disease control after salvage I-125 LDR-BT. In well-selected patients, I-125 LDR-BT is comparable to other salvage therapies in terms of disease control and toxicity. However, more research is needed to determine the optimal management of locally-recurrent prostate cancer.     

Changes in prostate cancer incidence,mortality and survival in relation to prostate specific antigen testing in New South Wales,Australia

BackgroundTo examine changes in prostate cancer incidence and mortality rates, and 5-year relative survival, in relation to changes in the rate of prostate specific antigen (PSA) screening tests and the use of radical prostatectomy (RP) in the Australian population.MethodsProstate cancer stage-specific incidence rates, 5-year relative survival and mortality rates were estimated using New South Wales Cancer Registry data. PSA screening test rates and RP/Incidence ratios were estimated from Medicare Benefits Schedule claims data. We used multiple imputation to impute stage for cases with “unknown” stage at diagnosis. Annual percentage changes (APC) in rates were estimated using Joinpoint regression.ResultsTrends in the age-standardized incidence rates for localized disease largely mirrored the trends in PSA screening test rates, with a substantial ‘spike’ in the rates occurring in 1994, followed by a second ‘spike’ in 2008, and then a significant decrease from 2008 to 2015 (APC −6.7, 95% CI −8.2, −5.1). Increasing trends in incidence rates were observed for regional stage from the early 2000s, while decreasing or stable trends were observed for distant stage since 1993. The overall RP/Incidence ratio increased from 1998 to 2003 (APC 9.6, 95% CI 3.8, 15.6), then remained relatively stable to 2015. The overall 5-year relative survival for prostate cancer increased from 58.4% (95% CI: 55.0–61.7%) in 1981–1985 to 91.3% (95% CI: 90.5–92.1%) in 2011–2015. Prostate cancer mortality rates decreased from 1990 onwards (1990–2006: APC −1.7, 95% CI −2.1, −1.2; 2006–2017: APC −3.8, 95% CI −4.4, −3.1).ConclusionsOverall, there was a decrease in the incidence rate of localized prostate cancer after 2008, an increase in survival over time and a decrease in the mortality rate since the 1990s. This seems to indicate that the more conservative use of PSA screening tests in clinical practice since 2008 has not had a negative impact on population-wide prostate cancer outcomes.     

Uroncor consensus statement: Management of biochemical recurrence after radical radiotherapy for prostate cancer: From biochemical failure to castration resistance

Management of patients who experience biochemical failure after radical radiotherapy with or without hormonal therapy is highly challenging. The clinician must not only choose the type of treatment, but also the timing and optimal sequence of treatment administration. When biochemical failure occurs, numerous treatment scenarios are possible, thus making it more difficult to select the optimal approach. Moreover, rapid and ongoing advances in treatment options require that physicians make decisions that could impact both survival and quality of life.The aim of the present consensus statement, developed by the Urological Tumour Working Group (URONCOR) of the Spanish Society of Radiation Oncology (SEOR), is to provide cancer specialists with the latest, evidence-based information needed to make the best decisions for the patient under all possible treatment scenarios.The structure of this consensus statement follows the typical development of disease progression after biochemical failure, with the most appropriate treatment recommendations given for each stage. The consensus statement is organized into three separate chapters, as follows: biochemical failure with or without local recurrence and/or metastasis; progression after salvage therapy; and treatment of castration-resistant patients.     

Positive prostate biopsy following radiotherapy can predict metastasis-free survival in localized prostate cancer

Background/aim(s)To determine the impact of post-treatment biopsy results on 10-year metastasis-free survival (MFS), overall survival (OS) and cause-specific survival (CSS) in localized prostate cancer (PCa) patients treated with high-dose radiotherapy (RT).Materials/MethodsRetrospective analysis of 232 patients with T1c-T3bN0M0 PCa who underwent a prostate biopsy 24–36 months after high-dose RT. Biopsies were categorized as positive biopsy (PB) if H&E staining showed evidence of residual malignancy and negative biopsy (NB) if no malignant cells were present. Kaplan-Meier estimates of 10-year MFS, OS and CSS rates were calculated for each group and Cox proportional-hazards models were used to estimate the hazard ratios. The median follow-up was 124 months (range 26–267).ResultsSixty-two of 232 (26.7%) patients had post-treatment positive biopsies (PB). A positive post-treatment biopsy was significantly associated with a lower 10-year MFS (78.4% vs. 95.4%, p = 0.001, HR: 3.9, 95% CI: 1.8–8.3). Although patients with PB had worse outcomes that those with NB, we could not show a statistically significant difference in OS (81.0% vs. 87.9%, p = 0.282, HR: 1.3, 95% CI: 0.7–2.3) or CSS (96.2% vs. 99.4% (p = 0.201, HR. 2.4, 95% CI: 0.6–9.7). After multivariate analysis, the strongest predictor of MFS was the post-treatment biopsy status (p < 0.001, HR: 5.4, 95% CI 2.26–12.85) followed by Gleason score (p = 0.002, HR: 2.24, 95% CI 1.33–3.79).ConclusionA positive biopsy following RT can predict MFS in localized prostate cancer. These data highlight the relevance of achieving a local control and support the use of aggressive local therapeutic interventions for PCa.     

Phase I dose escalation trial of stereotactic radiotherapy prior to robotic prostatectomy in high risk prostate cancer

BackgroundThe aim of the study was to investigate the safety of combining preoperative stereotactic body radiotherapy (SBRT) with robotic radical prostatectomy (RP) for high risk prostate cancer (HRCaP). Many patients with HRCaP will require adjuvant or salvage radiotherapy after RP. The addition of preoperative SBRT before RP may spare patients from subsequent prolonged courses of RT.Materials and methodsEligible patients had NCC N HRCaP and received a total of 25 Gy or 30 Gy in five daily fractions of SBRT to the prostate and seminal vesicles followed by robotic RP with pelvic lymphadenectomy 31–45 days later. The primary endpoint was prevalence of acute genitourinary (GU) and gastrointestinal (GI) toxicity. Secondary endpoints were patient-reported quality of life (QOL) and biochemical recurrence (BcR).ResultsThree patients received preoperative SBRT to 25 Gy and four received 30 Gy. Median follow-up was 18 months. Highest toxicity was grade 2 and 3 in six (85.7%) and one (14.3%) patients, respectively. All patients developed grade 2 erectile dysfunction and 4 of 7 (57%) developed grade 2 urinary incontinence (UI) within a month after surgery. One patient developed acute grade 3 UI, but there was no grade ≥ 4 toxicity. One patient experienced acute grade 2 hemorrhoidal bleeding. On QOL, acute GU complaints were common and peaked within 3 months. Bowel symptoms were mild. Two patients with pN+ experienced BcR.ConclusionsPreoperative SBRT before robotic RP in HRCaP is feasible and safe. The severity of acute GU toxicity with preoperative SBRT may be worse than RP alone, while bowel toxicity was mild.     

Techniques for adaptive prostate radiotherapy

Variations in the position and shape of the prostate make accurate setup and treatment challenging. Adaptive radiation therapy (ART) techniques seek to alter the treatment plan, at one or more points throughout the treatment course, in response to changes in patient anatomy observed between planning and pre-treatment images. This article reviews existing and developing ART techniques for prostate cancer along with an overview of supporting in-room imaging technologies. Challenges to the clinical implementation of adaptive radiotherapy are also discussed.     

Biochemical failure and toxicity in treatment with brachytherapy and external beam radiotherapy compared with radical prostatectomy in localized prostate cancer

BackgroundLocalized prostate cancer (T1–3N0M0) has therapeutic options such as radical prostatectomy (RP), external beam radiation therapy (EBRT) and brachytherapy (BT). However, the evidence of the outcome of these treatments is limited and no studies have been conducted comparing biochemical failure (BF) and toxicity associated with surgical treatment and EBRT + high-dose brachytherapy (HDBT) in the region.Materials and methodsRetrospective cohort study, clinical records of patients diagnosed with localized prostate cancer between 2014 and 2018 were reviewed at one of the main private neoplasm centers in Lima, Peru; Cox regression was used for both the BF outcome and the grade 2 toxicity outcome, calculating the hazard ratio (HR) with 95% confodence interval (CI).ResultsOf 549 patients, 76.3% (419) received RP as primary treatment, and 72% were between 50 and 70 years old at the time of diagnosis. The patients treated with EBRT + HDBT presented worse characteristics. The EBRT + HDBT group had a 40% lower risk of presenting BF (HR = 0.6; 95% CI: 0.4–0.9), and also a 50% greater risk of presenting toxicity greater than or equal to grade 2 (HR = 1.5; 95% CI: 1.0–2.0) than the group treated with RP.ConclusionOur results show that when comparing patients treated with EBRT + HDBT and RP, BF was greater in RP, and post-treatment toxicity was greater in EBRT + HDBT.     

Implementation of intensity modulated radiotherapy for prostate cancer in a private radiotherapy service in Mexico

Intensity modulated radiation therapy (IMRT) allows physicians to deliver higher conformal doses to the tumour, while avoiding adjacent structures. As a result the probability of tumour control is higher and toxicity may be reduced. However, implementation of IMRT is highly complex and requires a rigorous quality assurance (QA) program both before and during treatment. The present article describes the process of implementing IMRT for localized prostate cancer in a radiation therapy department. In our experience, IMRT implementation requires careful planning due to the need to simultaneously implement specialized software, multifaceted QA programs, and training of the multidisciplinary team. Establishing standardized protocols and ensuring close collaboration between a multidisciplinary team is challenging but essential.     

Predicting toxicity in radiotherapy for prostate cancer

This comprehensive review addresses most organs at risk involved in planning optimization for prostate cancer. It can be considered an update of a previous educational review that was published in 2009 (Fiorino et al., 2009).The literature was reviewed based on PubMed and MEDLINE database searches (from January 2009 up to September 2015), including papers in press; for each section/subsection, key title words were used and possibly combined with other more general key-words (such as radiotherapy, dose-volume effects, NTCP, DVH, and predictive model). Publications generally dealing with toxicity without any association with dose–volume effects or correlations with clinical risk factors were disregarded, being outside the aim of the review.A focus was on external beam radiotherapy, including post-prostatectomy, with conventional fractionation or moderate hypofractionation (<4 Gy/fraction); extreme hypofractionation is the topic of another paper in this special issue. Gastrointestinal and urinary toxicity are the most investigated endpoints, with quantitative data published in the last 5 years suggesting both a dose–response relationship and the existence of a number of clinical/patient related risk factors acting as dose–response modifiers. Some results on erectile dysfunction, bowel toxicity and hematological toxicity are also presented.     

Novel knowledge-based treatment planning model for hypofractionated radiotherapy of prostate cancer patients

PurposeTo demonstrate the strength of an innovative knowledge-based model-building method for radiotherapy planning using hypofractionated, multi-target prostate patients.Material and methodsAn initial RapidPlan model was trained using 48 patients who received 60 Gy to prostate (PTV60) and 44 Gy to pelvic nodes (PTV44) in 20 fractions. To improve the model's goodness-of-fit, an intermediate model was generated using the dose-volume histograms of best-spared organs-at-risk (OARs) of the initial model. Using the intermediate model and manual tweaking, all 48 cases were re-planned. The final model, trained using these re-plans, was validated on 50 additional patients. The validated final model was used to determine any planning advantage of using three arcs instead of two on 16 VMAT cases and tested on 25 additional cases to determine efficacy for single-PTV (PTV60-only) treatment planning.ResultsFor model validation, PTV V_95% of 99.9% was obtained by both clinical and knowledge-based planning. D_1% was lower for model plans: by 1.23 Gy (PTV60, CI = [1.00, 1.45]), and by 2.44 Gy (PTV44, CI = [1.72, 3.16]). OAR sparing was superior for knowledge-based planning: ΔD_mean = 3.70 Gy (bladder, CI = [2.83, 4.57]), and 3.22 Gy (rectum, CI = [2.48, 3.95]); ΔD_2% = 1.17 Gy (bowel bag, CI = [0.64, 1.69]), and 4.78 Gy (femoral heads, CI = [3.90, 5.66]). Using three arcs instead of two, improvements in OAR sparing and PTV coverage were statistically significant, but of magnitudes < 1 Gy. The model failed at reliable DVH predictions for single PTV plans.ConclusionsOur knowledge-based model delivers efficient, consistent plans with excellent PTV coverage and improved OAR sparing compared to clinical plans.     

Effects of MRI image normalization techniques in prostate cancer radiomics

The variance in intensities of MRI scans is a fundamental impediment for quantitative MRI analysis. Intensity values are not only highly dependent on acquisition parameters, but also on the subject and body region being scanned. This warrants the need for image normalization techniques to ensure that intensity values are consistent within tissues across different subjects and visits. Many intensity normalization methods have been developed and proven successful for the analysis of brain pathologies, but evaluation of these methods for images of the prostate region is lagging.In this paper, we compare four different normalization methods on 49 T2-w scans of prostate cancer patients: 1) the well-established histogram normalization, 2) the generalized scale normalization, 3) an extension of generalized scale normalization called generalized ball-scale normalization, and 4) a custom normalization based on healthy prostate tissue intensities. The methods are compared qualitatively and quantitatively in terms of behaviors of intensity distributions as well as impact on radiomic features.Our findings suggest that normalization based on prior knowledge of the healthy prostate tissue intensities may be the most effective way of acquiring the desired properties of normalized images. In addition, the histogram normalization method outperform the generalized scale and generalized ball-scale methods which have proven superior for other body regions.     

Evaluation of 18F-PSMA-1007 PET/CT in prostate cancer patients with biochemical recurrence after radical prostatectomy

PurposeProstate-specific membrane antigen (PSMA) ligands targeting has shown promising results in staging of prostate cancer (PCa). The aim of present study was to evaluate the value of ¹⁸F-PSMA-1007 PET/CT in PCa patients with biochemical recurrence.Methods71 patients with PCa after radical prostatectomy (RP) were included in the present study. Median prostate-specific antigen (PSA) level was 1.27 ng/mL (range 0.01–67.40 ng/mL, n = 69). All patients underwent whole-body PET/CT imaging after injection of 333±38 MBq ¹⁸F-PSMA-1007. The distribution of PSMA-positive lesions was assessed. The influence of PSA level, androgen deprivation therapy and primary Gleason score on PSMA-positive finding and uptake of ¹⁸F-PSMA-1007 were evaluated.Results56 (79%) patients showed at least one pathological finding on ¹⁸F-PSMA-1007 PET/CT. The rates of positive scans were 50%, 80%, 100%, 100% among patients with PSA levels ≤0.5, 0.51–1.0, 1.1–2.0 and >2.0 ng/mL, respectively. The median Gleason score was 8 (range 7–10), and higher Gleason score (≤7 vs. ≥8) leads to higher detection rates (58.3% (14/24) vs. 88.9% (32/36), P = 0.006). The median SUVmax of positive findings in patients with PSA levels ≤0.5, 0.51–1.0, 1.1–2.0 and >2.0 ng/mL were 4.51, 4.27, 11.50 and 14.08, respectively. The median SUVmax in patients with PSA level >2.0 ng/mL was significantly higher than that in patients with PSA ≤2.0 ng/mL (14.08 vs. 6.13, P<0.001).Conclusion¹⁸F-PSMA-1007 PET/CT demonstrated a high detection rate for patients with a raised PSA level after radical prostatectomy even in patients with extremely low PSA level (eg. PSA level ≤0.5 ng/mL), which was essential for further clinical management for PCa patients.     

Volumetric image-guided conformal radiotherapy for localized prostate cancer: Analysis of dosimetric and clinical factors affecting acute and late toxicity

Aim

To identify factors influencing toxicity in patients affected by localized prostate cancer treated with conformal image-guided radiotherapy.

Selecting proper combination of mpMRI sequences for prostate cancer classification using multi-input convolutional neuronal network

PurposeThis study aims to develop a deep-learning-based method to classify clinically significant (CS) and clinically insignificant (CiS) prostate cancer (PCa) on multiparametric magnetic resonance imaging (mpMRI) automatically, and to select suitable mpMRI sequences for PCa classification in different anatomic zones.MethodsA multi-input selection network (MISN) is proposed for both PCa classification and the selection of the optimal combination of sequences for PCa classification in a specific zone. MISN is a multi-input/-output classification network consisting of nine branches to process nine input images from the mpMRI data. To improve classification accuracy and reduce model parameters, a pruning strategy is proposed to select a subset of the nine branches of MIST to form two more effective networks for the peripheral zone (PZ) PCa and transition zone (TZ) PCa, which are named as PZN and TZN, respectively. Besides, a new penalized cross-entropy loss function is adopted to train the networks to balance the classification sensitivity and specificity.ResultsThe proposed methods were evaluated on the PROSTATEx challenge dataset and achieved an area under the receiver operator characteristics curve of 0.95, which was much higher than currently published results and ranked first out of more than 1500 entries submitted to the challenge at the time of submission of this paper. For PZ-PCa and TZ-PCa classification, PZN and TZN achieved better performance than MISN.ConclusionsHigher performance can be achieved by selecting a suitable subset of the mpMRI sequences in PCa classification.     

Stereotactic ablative radiotherapy for oligometastatic prostate cancer

BackgroundThe present study assessed clinical outcomes of stereotactic body radiotherapy (SBRT) in oligometastatic prostate cancer patients.Materials and methodsBetween 2017 and 2020, 37 lesions (12 osseous and 25 nodal targets) detected with conventional and/or functional imaging, were treated in 29 patients (pts), in different clinical settings: de novo oligometastatic (2 pts), oligorecurrent castration-sensitive (19 pts), castration-resistant (6 pts) prostate cancers and oligoprogressive disease during systemic therapy (2 pts). SBRT was delivered with volumetric modulated arc therapy up to a total dose of 21 Gy given in 3 fractions for bone and 30 Gy in 5 fractions for nodal metastases. A total of 34% of pts received hormonal therapy. We evaluated biochemical control [prostate serum antigen (PSA) increase < 10%)], progression free-survival (PFS) (time from SBRT to biochemical progression), local control (LC) (time from SBRT to in-field radiologic progression), hormone/systemic therapy-free survival, acute and late toxicities.ResultsAt 3 months, biochemical response was observed in 20/29 pts (69%). At a median follow-up of 17 months (range 6–33), 8/20 (40%) of the 3-month responders remained free from progression. Two-year PFS and LC were 37% and 70%, respectively. In-field progression occurred in 3/37 (8%) lesions. Hormone/systemic therapy was delayed by an average of 11.6 months (range 3–28). No significant difference in PFS based on the type of lesion or concomitant endocrine therapy was observed and no toxicity > grade 2 was reported.ConclusionsSBRT for oligometastatic prostate cancer offers a good biochemical/local control and tangible delay of hormone/systemic therapy without major toxicities.