Focal Salvage MR Imaging-Guided Cryoablation for Localized Prostate Cancer Recurrence after Radiotherapy: 12-Month Follow-up.

PURPOSE: To evaluate safety, quality of life (QoL), and local cancer control after focal salvage MR imaging-guided cryoablation in patients with local recurrence of prostate cancer (PCa) after radiotherapy. MATERIALS AND METHODS: A retrospective, single-center study was performed in 62 patients with radiorecurrent PCa who underwent MR imaging-guided cryoablation since May 2011 with a follow-up ≥12 months in December 2017. Rates and descriptions of adverse events were reported. Ablation complications were classified according to the Clavien and SIR systems. Validated questionnaires were used to observe functional outcomes and QoL before therapy and 6 and 12 months after therapy. Cancer control was defined as no biochemical failure according to Phoenix criteria and no other clinical evidence for local or metastatic disease. RESULTS: All procedures were technically feasible. The number of complications requiring major therapy (Clavien grade 3b/4 or SIR grade D/E/F) was low (2 [3.2%] and 1 [1.6%], respectively). After 12 months, the International Consultation of Incontinence Questionnaire-Short Form (P < .001) and 5-item International Index of Erectile Function (P = .001) scores became significantly worse, indicating increased symptoms of incontinence and diminished erectile function, without compromising QoL. Six patients developed metastases within 6 months. After 12 months, 36 patients (63%) were disease-free. CONCLUSIONS: Focal salvage MR imaging-guided cryoablation is safe and is associated with a high technical success rate, preservation of QoL, and local PCa control. This treatment can be a reasonable alternative to salvage radical prostatectomy in properly selected patients with low morbidity and preservation of QoL; however, longer follow-up is needed.

A short-term intervention with selenium affects expression of genes implicated in the epithelial-to-mesenchymal transition in the prostate.

In parallel with the inconsistency in observational studies and chemoprevention trials, the mechanisms by which selenium affects prostate cancer risk have not been elucidated. We conducted a randomized, placebo-controlled trial to examine the effects of a short-term intervention with selenium on gene expression in non-malignant prostate tissue. Twenty-three men received 300 µg selenium per day in the form of selenized yeast (n=12) or a placebo (n=11) during 5 weeks. Prostate biopsies collected from the transition zone before and after intervention were analysed for 15 participants (n=8 selenium, n=7 placebo). Pathway analyses revealed that the intervention with selenium was associated with down-regulated expression of genes involved in cellular migration, invasion, remodeling and immune responses. Specifically, expression of well-established epithelial markers, such as E-cadherin and epithelial cell adhesion molecule EPCAM, was up-regulated, while the mesenchymal markers vimentin and fibronectin were down-regulated after intervention with selenium. This implies an inhibitory effect of selenium on the epithelial-to-mesenchymal transition (EMT). Moreover, selenium was associated with down-regulated expression of genes involved in wound healing and inflammation; processes which are both related to EMT. In conclusion, our explorative data showed that selenium affected expression of genes implicated in EMT in the transition zone of the prostate.

[Anorectal symptoms after prostate radiotherapy]. / Anorectale klachten na prostaatbestraling.

Prostate cancer is the most common cancer in Dutch men and has a relatively good survival rate. Anorectal symptoms after irradiation of the prostate, including rectal blood loss and faecal incontinence, can have a serious impact on quality of life. On endoscopy, the Vienna Rectoscopy Score may reveal telangiectasia or other mucosal changes, but there may also be other causes of blood loss. Endoscopy or watchful waiting can be considered in patients with rectal bleeding. Sucralfate enemas, argon plasma coagulation and hyperbaric oxygen therapy are effective treatments. Increase in frequency of defaecation, faecal urgency or incontinence are related to decreased rectal compliance or to lowered anal resting pressure. Dietary measures can be considered in patients with faecal urgency or incontinence, but scientific evidence for the effectiveness of this is marginal. More accurate radiation techniques and the use of a spacer or endorectal balloon will probably contribute to maintaining rectal and anal function.

Systematic review: anal and rectal changes after radiotherapy for prostate cancer.

PURPOSE: Pelvic radiotherapy may lead to changes of anorectal function resulting in incontinence-related complaints. The aim of this study was to systematically review objective findings of late anorectal physiology and mucosal appearance after irradiation for prostate cancer. METHODS: MEDLINE, EMBASE, and the Cochrane library were searched. Original articles in which anal function, rectal function, or rectal mucosa were examined ≥3 months after EBRT for prostate cancer were included. RESULTS: Twenty-one studies were included with low to moderate quality. Anal resting pressures significantly decreased in 6 of the 9 studies including 277 patients. Changes of squeeze pressure and rectoanal inhibitory reflex were less uniform. Rectal distensibility was significantly impaired after EBRT in 7 of 9 studies (277 patients). In 4 of 9 studies on anal and in 5 of 9 on rectal function, disturbances were associated with urgency, frequent bowel movements or fecal incontinence. Mucosal changes as assessed by the Vienna Rectoscopy Score revealed telangiectasias in 73 %, congestion in 33 %, and ulceration in 4 % of patients in 8 studies including 346 patients, but no strictures or necrosis. Three studies reported mucosal improvement during follow-up. Telangiectasias, particularly multiple, were associated with rectal bleeding. Not all bowel complaints (30 %) were related to radiotherapy. CONCLUSIONS: Low to moderate quality evidence indicates that EBRT reduces anal resting pressure, decreases rectal distensibility, and frequently induces telangiectasias of rectal mucosa. Objective changes may be associated with fecal incontinence, urgency, frequent bowel movements, and rectal bleeding, but these symptoms are not always related to radiation damage.

Impact of late anorectal dysfunction on quality of life after pelvic radiotherapy.

PURPOSE: Anorectal dysfunction is common after pelvic radiotherapy. This study aims to explore the relationship of subjective and objective anorectal function with quality of life (QoL) and their relative impact in patients irradiated for prostate cancer. METHODS: Patients underwent anal manometry, rectal barostat measurement, and completed validated questionnaires, at least 1 year after prostate radiotherapy (range 1-7 years). QoL was measured by the Fecal Incontinence Quality of Life scale (FIQL) and the Expanded Prostate Cancer Index Composite Bowel domain (EPICB)-bother subscale. Severity of symptoms was rated by the EPICB function subscale. RESULTS: Anorectal function was evaluated in 85 men. Sixty-three percent suffered from one or more anorectal symptoms. Correlations of individual symptoms ranged from r = 0.23 to r = 0.53 with FIQL domains and from r = 0.36 to r = 0.73 with EPICB bother scores. They were strongest for fecal incontinence and urgency. Correlations of anal sphincter pressures, rectal capacity, and sensory thresholds ranged from r = 0.00 to r = 0.42 with FIQL domains and from r = 0.15 to r = 0.31 with EPICB bother scores. Anal resting pressure correlated most strongly. Standardized regression coefficients for QoL outcomes were largest for incontinence, urgency, and anal resting pressure. Regression models with subjective parameters explained a larger amount (range 26-92 %) of variation in QoL outcome than objective parameters (range 10-22 %). CONCLUSIONS: Fecal incontinence and rectal urgency are the symptoms with the largest influence on QoL. Impaired anal resting pressure is the objective function parameter with the largest influence. Therefore, sparing the structures responsible for an adequate fecal continence is important in radiotherapy planning.

Geographical distribution of lymph node metastases on MR lymphography in prostate cancer patients.

PURPOSE: To investigate the pattern of lymph node spread on magnetic resonance lymphography (MRL) in prostate cancer patients and compare this pattern to the clinical target volume for elective pelvis irradiation as defined by the radiation therapy oncology group (RTOG-CTV). METHODS AND MATERIALS: The charts of 60 intermediate and high risk prostate cancer patients with non-enlarged positive lymph nodes on MRL were reviewed. Positive lymph nodes were assigned to a lymph node region according to the guidelines for delineation of the RTOG-CTV. Five lymph node regions outside this RTOG-CTV were defined: the para-aortal, proximal common iliac, pararectal, paravesical and inguinal region. RESULTS: Fifty-three percent of the patients had an MRL-positive lymph node in a lymph node region outside the RTOG-CTV. The most frequently involved aberrant sites were the proximal common iliac, the pararectal and para-aortal region, which were affected in 30%, 25% and 18% respectively. CONCLUSION: More than half of the patients had an MRL-positive lymph node outside the RTOG-CTV. To reduce geographical miss while minimizing the toxicity of radiotherapy, image based definition of an individual target volume seems to be necessary.

Single blind randomized phase III trial to investigate the benefit of a focal lesion ablative microboost in prostate cancer (FLAME-trial): study protocol for a randomized controlled trial.

BACKGROUND: The treatment results of external beam radiotherapy for intermediate and high risk prostate cancer patients are insufficient with five-year biochemical relapse rates of approximately 35%. Several randomized trials have shown that dose escalation to the entire prostate improves biochemical disease free survival. However, further dose escalation to the whole gland is limited due to an unacceptable high risk of acute and late toxicity. Moreover, local recurrences often originate at the location of the macroscopic tumor, so boosting the radiation dose at the macroscopic tumor within the prostate might increase local control. A reduction of distant metastases and improved survival can be expected by reducing local failure. The aim of this study is to investigate the benefit of an ablative microboost to the macroscopic tumor within the prostate in patients treated with external beam radiotherapy for prostate cancer. METHODS/DESIGN: The FLAME-trial (Focal Lesion Ablative Microboost in prostatE cancer) is a single blind randomized controlled phase III trial. We aim to include 566 patients (283 per treatment arm) with intermediate or high risk adenocarcinoma of the prostate who are scheduled for external beam radiotherapy using fiducial markers for position verification. With this number of patients, the expected increase in five-year freedom from biochemical failure rate of 10% can be detected with a power of 80%. Patients allocated to the standard arm receive a dose of 77 Gy in 35 fractions to the entire prostate and patients in the experimental arm receive 77 Gy to the entire prostate and an additional integrated microboost to the macroscopic tumor of 95 Gy in 35 fractions. The secondary outcome measures include treatment-related toxicity, quality of life and disease-specific survival. Furthermore, by localizing the recurrent tumors within the prostate during follow-up and correlating this with the delivered dose, we can obtain accurate dose-effect information for both the macroscopic tumor and subclinical disease in prostate cancer. The rationale, study design and the first 50 patients included are described. TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov: NCT01168479.

Depression related to (neo)adjuvant hormonal therapy for prostate cancer.

BACKGROUND: We studied whether hormonal therapy, (neo)adjuvant to radiotherapy for localized prostate cancer, is related to an increase in depression and whether this is caused by the hormonal therapy itself or by the relatively poor prognosis of patients who get (neo)adjuvant hormonal therapy. METHODS: Between 2002 and 2005, 288 patients, irradiated for prostate cancer (T1-3N0M0), were studied prospectively in two clinics. In one clinic almost all patients received (neo)adjuvant androgen deprivation (Bicalutamide+Gosereline). In a second clinic hormonal therapy was prescribed mainly for high risk patients. This allowed us to separate the effects of hormonal therapy and the patient's prognosis. RESULTS: During the course of hormonal therapy, depression was significantly heightened by both hormone use (p<0.001) and poor prognosis (p<0.01). After completion of hormonal therapy, poor prognosis continued to affect the depression score (p<0.01). The increase was, however, small. CONCLUSIONS: Depression was mildly increased in patients receiving hormonal therapy. The increase appeared to be related to both the hormone therapy itself and the high risk status of patients. High risk status, with the associated poor prognosis, had a more sustained effect on depression. The rise was statistically significant, but was too small, however, to bear clinical significance.

Comparison of nodal risk formula and MR lymphography for predicting lymph node involvement in prostate cancer.

PURPOSE: To compare the nodal risk formula (NRF) as a predictor for lymph node (LN) metastasis in patients with prostate cancer with magnetic resonance lymphography (MRL) using Ultrasmall Super-Paramagnetic particles of Iron Oxide (USPIO) and with histology as gold standard. METHODS AND MATERIALS: Logistic regression analysis was performed with the results of histopathological evaluation of the LN as dependent variable and the nodal risk according to the NRF and the result of MRL as independent input variables. Receiver operating characteristic (ROC) analysis was performed to assess the performance of the models. RESULTS: The analysis included 375 patients. In the single-predictor regression models, the NRF and MRL results were both significantly (p<0.001) predictive of the presence of LN metastasis. In the models with both predictors included, NRF was nonsignificant (p=0.126), but MRL remained significant (p<0.001). For NRF, sensitivity was 0.79 and specificity was 0.38; for MRL, sensitivity was 0.82 and specificity was 0.93. After a negative MRL result, the probability of LN metastasis is 4% regardless of the NRF result. After a positive MRL, the probability of having LN metastasis is 68%. CONCLUSIONS: MRL is a better predictor of the presence of LN metastasis than NRF. Using only the NRF can lead to a significant overtreatment on the pelvic LN by radiation therapy. When the MRL result is available, the NRF is no longer of added value.

Efficacy and tolerance of salvage radiotherapy after radical prostatectomy, with emphasis on high-risk patients suited for adjuvant radiotherapy.

BACKGROUND AND PURPOSE: Goals of this study are to report the outcomes and tolerance of salvage radiotherapy (SRT) after prostatectomy, to identify risk factors for failure after SRT and to evaluate how these results compare with published results of immediate post-operative adjuvant radiotherapy (ART). MATERIAL AND METHODS: Men receiving SRT for elevated PSA levels after radical prostatectomy (RP) were included. Biochemical progression-free survival (bPFS), overall survival (OS) and disease-specific survival (DSS) were estimated. Risk factors for biochemical failure and death were evaluated. Late toxicity and quality of life were evaluated. Secondary bPFS (defined as bPFS from prostatectomy until progression after radiotherapy) was calculated for high-risk patients (pT3 and/or positive surgical margins) in order to compare SRT outcomes with ART. RESULTS: 197 Men were included. Five-year bPFS after SRT was 59% (95% CI 49-69%). Five-year OS and DSS were 90% (85-96%) and 97% (93-100%), respectively. Capsular perforation (pT≥T3), negative surgical margins and serum PSA>1 ng/ml at the start of RT were significant predictors of lower bPFS. Patients without any negative factors had a 5-year bPFS of 89%. No severe late toxicity was reported. Five-year secondary bPFS for SRT in high-risk patients was 78% and comparable with published results for ART. CONCLUSIONS: Salvage radiotherapy for patients with organ-confined prostate cancer was effective and well tolerated. SRT outcomes were comparable with published ART results for high-risk patients. Initially monitoring serum PSA and considering early SRT for these patients are not harmful and might be a valuable alternative for immediate ART.

Changes in prostate shape and volume and their implications for radiotherapy after introduction of endorectal balloon as determined by MRI at 3T.

PURPOSE: To determine the changes in prostate shape and volume after the introduction of an endorectal coil (ERC) by means of magnetic resonance imaging (MRI) at 3T. METHODS AND MATERIALS: A total of 44 consecutive patients with biopsy-proven prostate cancer underwent separate MRI examinations at 3T with a body array coil and subsequently with an ERC inflated with 50 mL of fluid. Prospectively, two experienced readers independently evaluated all data sets in random order. The maximal anteroposterior, right-to-left, and craniocaudal prostate diameters, as well as the total prostate and peripheral zone and central gland volumes were measured before and after ERC introduction. The changes in prostate shape and volume were analyzed using Wilcoxon's test for paired samples. RESULTS: The introduction of the ERC significantly changed the prostate shape in all three directions, with mean changes in the anteroposterior, right-to-left, and craniocaudal diameters of 15.7% (5.5 mm), 7.7% (3.5 mm), and 6.3% (2.2 mm), respectively. The mean total prostate, peripheral zone, and central gland volume decreased significantly after ERC introduction by 17.9% (8.3 cm(3)), 21.6% (4.8 cm(3)), and 14.2% (3.4 cm(3)), respectively. CONCLUSION: ERC introduction as observed by 3T MRI changed the prostate shape and volume significantly. The mean anteroposterior diameter was reduced by nearly one-sixth of its original diameter, and the mean total prostate volume was decreased by approximately 18%. This could cause difficulties and should be considered when using ERC-based MRI for MRI-computed tomography fusion and radiotherapy planning.

Ultrasound-guided transrectal implantation of gold markers for prostate localization during external beam radiotherapy: complication rate and risk factors.

PURPOSE: To report the complication rate and risk factors of transrectally implanted gold markers, used for prostate position verification and correction procedures. METHODS AND MATERIALS: In 209 consecutive men with localized prostate cancer, four gold markers (1 x 7 mm) were inserted under ultrasound guidance in an outpatient setting, and the toxicity was analyzed. All patients received a questionnaire regarding complications after marker implantation. The complications and risk factors were further evaluated by reviewing the medical charts. RESULTS: Of the 209 men, 13 (6.2%) had a moderate complication, consisting of pain and fever that resolved after treatment with oral medication. In 1.9% of the men, minor voiding complaints were observed. Other minor transient complications, defined as hematuria lasting >3 days, hematospermia, and rectal bleeding, occurred in 3.8%, 18.5%, and 9.1% of the patients, respectively. These complications were seen more often in patients with advanced tumor stage, younger age, and shorter duration of hormonal therapy. CONCLUSION: Transrectal gold marker implantation for high-precision prostate radiotherapy is a safe and well-tolerated procedure.

Do patients with localized prostate cancer treatment really want more aggressive treatment?

PURPOSE: Examine whether patients with prostate cancer choose the more aggressive of two radiotherapeutic options, whether this choice is reasoned, and what the determinants of the choice are. PATIENTS AND METHODS: One hundred fifty patients with primary prostate cancer (T(1-3)N(0)M(0)) were informed by means of a decision aid of two treatment options: radiotherapy with 70 Gy versus 74 Gy. The latter treatment is associated with more cure and more toxicity. The patients were asked whether they wanted to choose, and if so which treatment they preferred. They also assigned importance weights to the probability of various outcomes, such as survival, cure and adverse effects. Patients who wanted to choose their own treatment (n = 119) are described here. RESULTS: The majority of these patients (75%) chose the lower radiation dose. Their choice was highly consistent (P < or = .001), with the importance weights assigned to the probability of survival, cure (odds ratio [OR] = 6.7 and 6.9) and late GI and genitourinary adverse effects (OR = 0.1 and 0.2). The lower dose was chosen more often by the older patients, low-risk patients, patients without hormone treatment, and patients with a low anxiety or depression score. CONCLUSION: Most patients with localized prostate cancer prefer the lower radiation dose. Our findings indicate that many patients attach more weight to specific quality-of-life aspects (eg, GI toxicity) than to improving survival. Treatment preferences of patients with localized prostate cancer can and should be involved in radiotherapy decision making.

Do prostate cancer patients want to choose their own radiation treatment?

PURPOSE: The aims of this study were to investigate whether prostate cancer patients want to be involved in the choice of the radiation dose, and which patients want to be involved. METHODS AND MATERIALS: This prospective study involved 150 patients with localized prostate cancer treated with three-dimensional conformal radiotherapy. A decision aid was used to explain the effects of two alternative radiation doses (70 and 74 Gy) in terms of cure and side effects. Patients were then asked whether they wanted to choose their treatment (accept choice), or leave the decision to the physician (decline choice). The treatment preference was carried out. RESULTS: Even in this older population (mean age, 70 years), most patients (79%) accepted the option to choose. A lower score on the designations Pre-existent bowel morbidity, Anxiety, Depression, Hopelessness and a higher score on Autonomy and Numeracy were associated with an increase in choice acceptance, of which only Hopelessness held up in multiple regression (p < 0.03). The uninformed participation preference at baseline was not significantly related to choice acceptance (p = 0.10). CONCLUSION: Uninformed participation preference does not predict choice behavior. However, once the decision aid is provided, most patients want to choose their treatment. It should, therefore, be considered to inform patients first and ask participation preferences afterwards.

IMRT boost dose planning on dominant intraprostatic lesions: gold marker-based three-dimensional fusion of CT with dynamic contrast-enhanced and 1H-spectroscopic MRI.

PURPOSE: To demonstrate the theoretical feasibility of integrating two functional prostate magnetic resonance imaging (MRI) techniques (dynamic contrast-enhanced MRI [DCE-MRI] and 1H-spectroscopic MRI [MRSI]) into inverse treatment planning for definition and potential irradiation of a dominant intraprostatic lesion (DIL) as a biologic target volume for high-dose intraprostatic boosting with intensity-modulated radiotherapy (IMRT). METHODS AND MATERIALS: In 5 patients, four gold markers were implanted. An endorectal balloon was inserted for both CT and MRI. A DIL volume was defined by DCE-MRI and MRSI using different prostate cancer-specific physiologic (DCE-MRI) and metabolic (MRSI) parameters. CT-MRI registration was performed automatically by matching three-dimensional gold marker surface models with the iterative closest point method. DIL-IMRT plans, consisting of whole prostate irradiation to 70 Gy and a DIL boost to 90 Gy, and standard IMRT plans, in which the whole prostate was irradiated to 78 Gy were generated. The tumor control probability and rectal wall normal tissue complication probability were calculated and compared between the two IMRT approaches. RESULTS: Combined DCE-MRI and MRSI yielded a clearly defined single DIL volume (range, 1.1-6.5 cm3) in all patients. In this small, selected patient population, no differences in tumor control probability were found. A decrease in the rectal wall normal tissue complication probability was observed in favor of the DIL-IMRT plan versus the plan with IMRT to 78 Gy. CONCLUSION: Combined DCE-MRI and MRSI functional image-guided high-dose intraprostatic DIL-IMRT planned as a boost to 90 Gy is theoretically feasible. The preliminary results have indicated that DIL-IMRT may improve the therapeutic ratio by decreasing the normal tissue complication probability with an unchanged tumor control probability. A larger patient population, with more variations in the number, size, and localization of the DIL, and a feasible mechanism for treatment implementation has to be studied to extend these preliminary tumor control and toxicity estimates.

Systematic review of the effect of radiation dose on tumor control and morbidity in the treatment of prostate cancer by 3D-CRT.

PURPOSE: A higher radiation dose is believed to result in a larger probability of tumor control and a higher risk of side effects. To make an evidence-based choice of dose, the relation between dose and outcome needs to be known. This study focuses on the dose-response relation for prostate cancer. METHODS AND MATERIALS: A systematic review was carried out on the literature from 1990 to 2003. From the selected studies, the radiation dose, the associated 5-year survival, 5-year bNED (biochemical no evidence of disease), acute and late gastrointestinal (GI) and genitourinary (GU) morbidity Grade 2 or more, and sexual dysfunction were extracted. With logistic regression models, the relation between dose and outcome was described. RESULTS: Thirty-eight studies met our criteria, describing 87 subgroups and involving up to 3000 patients per outcome measure. Between the (equivalent) dose of 70 and 80 Gy, various models estimated an increase in 5-year survival (ranging from 10% to 11%), 5-year bNED for low-risk patients (5-7%), late GI complications (12-16%), late GU complications (8-10%), and erectile dysfunction (19-24%). Only for the overall 5-year bNED, results were inconclusive (range, 0-18%). CONCLUSIONS: The data suggest a relationship between dose and outcome measures, including survival. However, the strength of these conclusions is limited by the sometimes small number of studies, the incompleteness of the data, and above all, the correlational nature of the data. Unambiguous proof for the dose-response relationships can, therefore, only be obtained by conducting randomized trials.

Prostate cancer: precision of integrating functional MR imaging with radiation therapy treatment by using fiducial gold markers.

The use of intensity-modulated radiation therapy for treatment of dominant intraprostatic lesions may require integration of functional magnetic resonance (MR) imaging with treatment-planning computed tomography (CT). The purpose of this study was to compare prospectively the landmark and iterative closest point methods for registration of CT and MR images of the prostate gland after placement of fiducial markers. The study was approved by the institutional ethics review board, and informed consent was obtained. CT and MR images were registered by using fiducial gold markers that were inserted into the prostate. Two image registration methods--a commonly available landmark method and dedicated iterative closest point method--were compared. Precision was assessed for a data set of 21 patients by using five operators. Precision of the iterative closest point method (1.1 mm) was significantly better (P < .01) than that of the landmark method (2.0 mm). Furthermore, a method is described by which multimodal MR imaging data are reduced into a single interpreted volume that, after registration, can be incorporated into treatment planning.