Publications by authors named "Almudena Zapatero"

39 Publications

Oligorecurrent nodal prostate cancer: Radiotherapy quality assurance of the randomized PEACE V-STORM phase II trial.

Radiother Oncol 2022 Apr 26;172:1-9. Epub 2022 Apr 26.

Department of Radiation Oncology, Geneva University Hospital, Switzerland. Electronic address:

Purpose: Aim of this study is to report the results of the radiotherapy quality assurance program of the PEACE V-STORM randomized phase II trial for pelvic nodal oligorecurrent prostate cancer (PCa).

Material And Methods: A benchmark case (BC) consisting of a postoperative case with 2 nodal recurrences was used for both stereotactic body radiotherapy (SBRT, 30 Gy/3 fx) and whole pelvic radiotherapy (WPRT, 45 Gy/25 fx + SIB boost to 65 Gy).

Results: BC of 24 centers were analyzed. The overall grading for delineation variation of the 1st BC was rated as 'UV' (Unacceptable Variation) or 'AV' (Acceptable Variation) for 1 and 7 centers for SBRT (33%), and 3 and 8 centers for WPRT (46%), respectively. An inadequate upper limit of the WPRT CTV (n = 2), a missing delineation of the prostate bed (n = 1), and a missing nodal target volume (n = 1 for SBRT and WPRT) constituted the observed 'UV'. With the 2nd BC (n = 11), the overall delineation review showed 2 and 8 'AV' for SBRT and WPRT, respectively, with no 'UV'. For the plan review of the 2nd BC, all treatment plans were per protocol for WPRT. SBRT plans showed variability in dose normalization (Median D = 30.1 Gy, range 22.9-33.2 Gy and 30.6 Gy, range 26.8-34.2 Gy for nodes 1 and 2 respectively).

Conclusions: Up to 46% of protocol deviations were observed in delineation of WPRT for nodal oligorecurrent PCa, while dosimetric results of SBRT showed the greatest disparities between centers. Repeated BC resulted in an improved adherence to the protocol, translating in an overall acceptable contouring and planning compliance rate among participating centers.
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http://dx.doi.org/10.1016/j.radonc.2022.04.020DOI Listing
April 2022

High-dose Radiotherapy or Androgen Deprivation Therapy (HEAT) as Treatment Intensification for Localized Prostate Cancer: An Individual Patient-data Network Meta-analysis from the MARCAP Consortium.

Eur Urol 2022 Apr 22. Epub 2022 Apr 22.

Hospital General Universitario Gregorio Marañón, Madrid, Spain.

Background: The relative benefits of radiotherapy (RT) dose escalation and the addition of short-term or long-term androgen deprivation therapy (STADT or LTADT) in the treatment of prostate cancer are unknown.

Objective: To perform a network meta-analysis (NMA) of relevant randomized trials to compare the relative benefits of RT dose escalation ± STADT or LTADT.

Design, Setting, And Participants: An NMA of individual patient data from 13 multicenter randomized trials was carried out for a total of 11862 patients. Patients received one of the six permutations of low-dose RT (64 to <74 Gy) ± STADT or LTADT, high-dose RT (≥74 Gy), or high-dose RT ± STADT or LTADT.

Outcome Measurements And Statistical Analyses: Metastasis-free survival (MFS) was the primary endpoint. Frequentist and Bayesian NMAs were performed to rank the various treatment strategies by MFS and biochemical recurrence-free survival (BCRFS).

Results And Limitations: Median follow-up was 8.8 yr (interquartile range 5.7-11.5). The greatest relative improvement in outcomes was seen for addition of LTADT, irrespective of RT dose, followed by addition of STADT, irrespective of RT dose. RT dose escalation did not improve MFS either in the absence of ADT (hazard ratio [HR] 0.97, 95% confidence interval [CI] 0.80-1.18) or with STADT (HR 0.99, 95% CI 0.8-1.23) or LTADT (HR 0.94, 95% CI 0.65-1.37). According to P-score ranking and rankogram analysis, high-dose RT + LTADT was the optimal treatment strategy for both BCRFS and longer-term outcomes.

Conclusions: Conventionally escalated RT up to 79.2 Gy, alone or in the presence of ADT, does not improve MFS, while addition of STADT or LTADT to RT alone, regardless of RT dose, consistently improves MFS. RT dose escalation does provide a high probability of improving BCRFS and, provided it can be delivered without compromising quality of life, may represent the optimal treatment strategy when used in conjunction with ADT.

Patient Summary: Using a higher radiotherapy dose when treating prostate cancer does not reduce the chance of developing metastases or death, but it does reduce the chance of having a rise in prostate-specific antigen (PSA) signifying recurrence of cancer. Androgen deprivation therapy improves all outcomes. A safe increase in radiotherapy dose in conjunction with androgen deprivation therapy may be the optimal treatment.
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http://dx.doi.org/10.1016/j.eururo.2022.04.003DOI Listing
April 2022

Management of Patients with Advanced Prostate Cancer: Report from the Advanced Prostate Cancer Consensus Conference 2021.

Eur Urol 2022 Apr 18. Epub 2022 Apr 18.

Department of Oncology and Radiotherapy, Innlandet Hospital Trust, Gjøvik, Norway.

Background: Innovations in treatments, imaging, and molecular characterisation in advanced prostate cancer have improved outcomes, but various areas of management still lack high-level evidence to inform clinical practice. The 2021 Advanced Prostate Cancer Consensus Conference (APCCC) addressed some of these questions to supplement guidelines that are based on level 1 evidence.

Objective: To present the voting results from APCCC 2021.

Design, Setting, And Participants: The experts identified three major areas of controversy related to management of advanced prostate cancer: newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC), the use of prostate-specific membrane antigen ligands in diagnostics and therapy, and molecular characterisation of tissue and blood. A panel of 86 international prostate cancer experts developed the programme and the consensus questions.

Outcome Measurements And Statistical Analysis: The panel voted publicly but anonymously on 107 pre-defined questions, which were developed by both voting and non-voting panel members prior to the conference following a modified Delphi process.

Results And Limitations: The voting reflected the opinions of panellists and did not incorporate a standard literature review or formal meta-analysis. The answer options for the consensus questions received varying degrees of support from panellists, as reflected in this article and the detailed voting results reported in the Supplementary material.

Conclusions: These voting results from a panel of experts in advanced prostate cancer can help clinicians and patients to navigate controversial areas of management for which high-level evidence is scant. However, diagnostic and treatment decisions should always be individualised according to patient characteristics, such as the extent and location of disease, prior treatment(s), comorbidities, patient preferences, and treatment recommendations, and should also incorporate current and emerging clinical evidence and logistic and economic constraints. Enrolment in clinical trials should be strongly encouraged. Importantly, APCCC 2021 once again identified salient questions that merit evaluation in specifically designed trials.

Patient Summary: The Advanced Prostate Cancer Consensus Conference is a forum for discussing current diagnosis and treatment options for patients with advanced prostate cancer. An expert panel votes on predefined questions focused on the most clinically relevant areas for treatment of advanced prostate cancer for which there are gaps in knowledge. The voting results provide a practical guide to help clinicians in discussing treatment options with patients as part of shared decision-making.
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http://dx.doi.org/10.1016/j.eururo.2022.04.002DOI Listing
April 2022

High-dose radiotherapy and risk-adapted androgen deprivation in localised prostate cancer (DART 01/05): 10-year results of a phase 3 randomised, controlled trial.

Lancet Oncol 2022 May 12;23(5):671-681. Epub 2022 Apr 12.

Radiation Oncology Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain; Radiation Oncology Department, Clínical Universitaria de Navarra, Madrid, Spain.

Background: The optimal duration of androgen deprivation combined with high-dose radiotherapy in prostate cancer remains controversial. The DART 01/05 trial was designed to determine whether long-term androgen deprivation is superior to short-term androgen deprivation when combined with high-dose radiotherapy. The 5-year results showed that 2 years of adjuvant androgen deprivation combined with high-dose radiotherapy significantly improved biochemical control, metastasis, and overall survival, especially in patients with high-risk disease. In this report, we present the 10-year final results of the trial.

Methods: This open-label, phase 3, randomised, controlled trial was done in ten hospitals in Spain. The eligibility criteria included patients aged 18 years or older with histologically confirmed T1c to T3, N0, and M0 adenocarcinoma of the prostate, according to the 2002 classification of the American Joint Committee on Cancer, with intermediate-risk and high-risk factors, prostate-specific antigen (PSA) less than 100 ng/mL, and a Karnofsky performance score of at least 70%. Patients were randomly assigned (1:1) to receive 4 months of neoadjuvant and concomitant short-term androgen deprivation (STAD) plus high-dose radiotherapy (minimum dose 76 Gy; median dose 78 Gy) or to receive the same treatment followed by 24 months of adjuvant long-term androgen deprivation (LTAD), via a randomisation scheduled generated by Statistical Analysis Software programme (version 9.1) and an interactive web response system. Patients assigned to the STAD group received 4 months of neoadjuvant and concomitant androgen deprivation (oral flutamide 750 mg per day or oral bicalutamide 50 mg per day) with subcutaneous goserelin (2 months before and 2 months combined with high-dose radiotherapy). Anti-androgen therapy was added during the first 2 months of treatment. Patients assigned to LTAD continued with goserelin every 3 months for another 24 months. The primary endpoint was biochemical disease-free survival at 5 years. For this 10-year study we analysed overall survival, metastasis-free survival, biochemical disease-free survival, and cause-specific survival. Analysis was by intention to treat. This trial is closed and is registered at ClinicalTrials.gov (NCT02175212) and in the EU Clinical Trials Register (EudraCT 2005-000417-36).

Findings: Between Nov 7, 2005, and Dec 20, 2010, 355 patients were enrolled. One patient in the STAD group withdrew from the trial, hence 354 participants were randomly assigned to STAD (n=177) or LTAD (n=177). The median follow-up was 119·4 months (IQR 100·6-124·3). The 10-year biochemical disease-free survival for LTAD was 70·2% (95% CI 63·1-77·3) and for STAD was 62·3% (54·9-69·7; hazard ratio [HR] 0·84; 95% CI 0·50-1·43; p=0·52). At 10 years, overall survival was 78·4% (72·1-84·8) for LTAD and 73·3% (66·6-80·0) for STAD (HR 0·84; 95% CI 0·55-1·27; p=0·40), and metastasis-free survival was 76·0% (69·4-82·7) for LTAD and 70·9% (64·0-77·8) for STAD (HR 0·90; 95% CI, 0·37-2·19; p=0·81). For the subgroup of high-risk patients, the 10-year biochemical disease-free survival was 67·2% (57·2-77·2) for LTAD and 53·7% (43·3-64·1) for STAD (HR 0·90; 95% CI 0·49-1·64; p=0·73), the 10-year overall survival was 78·5% (69·6-87·3) for LTAD and 67·0% (57·3-76·7) for STAD (HR 0·58; 95% CI 0·33-1·01; p=0·054), and the 10-year metastasis-free survival was 76·6% (95% CI 67·6-85·6) for LTAD and 65·0% (55·1-74·8) for STAD (HR 0·89; 95% CI 0·33-2·43; p=0·82). Only 11 (3%) of 354 patients died from prostate cancer, all of them in the high-risk subgroup (five in the LTAD group and six in the STAD group). 76 (21%) patients died from other causes (mainly second malignancies in 31 [9%] and cardiovascular disease in 21 [6%]). No treatment-related deaths were observed.

Interpretation: After an extended 10-year follow-up, we were unable to support the significant benefit of LTAD reported at 5 years. However, the magnitude of the benefit was clinically relevant in high-risk patients. Intermediate-risk patients treated with high-dose radiotherapy do not benefit from LTAD. A biological characterisation with the inclusion of genomic testing is needed in the decision-making process.

Funding: Grupo de Investigación en Oncología Radioterápica and Sociedad Española de Oncología Radioterápica, the National Health Investigation Fund, and AstraZeneca.
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http://dx.doi.org/10.1016/S1470-2045(22)00190-5DOI Listing
May 2022

What Experts Think About Prostate Cancer Management During the COVID-19 Pandemic: Report from the Advanced Prostate Cancer Consensus Conference 2021.

Eur Urol 2022 Feb 17. Epub 2022 Feb 17.

University of British Columbia, Vancouver, British Columbia, Canada.

Patients with advanced prostate cancer (APC) may be at greater risk for severe illness, hospitalisation, or death from coronavirus disease 2019 (COVID-19) due to male gender, older age, potential immunosuppressive treatments, or comorbidities. Thus, the optimal management of APC patients during the COVID-19 pandemic is complex. In October 2021, during the Advanced Prostate Cancer Consensus Conference (APCCC) 2021, the 73 voting members of the panel members discussed and voted on 13 questions on this topic that could help clinicians make treatment choices during the pandemic. There was a consensus for full COVID-19 vaccination and booster injection in APC patients. Furthermore, the voting results indicate that the expert's treatment recommendations are influenced by the vaccination status: the COVID-19 pandemic altered management of APC patients for 70% of the panellists before the vaccination was available but only for 25% of panellists for fully vaccinated patients. Most experts (71%) were less likely to use docetaxel and abiraterone in unvaccinated patients with metastatic hormone-sensitive prostate cancer. For fully vaccinated patients with high-risk localised prostate cancer, there was a consensus (77%) to follow the usual treatment schedule, whereas in unvaccinated patients, 55% of the panel members voted for deferring radiation therapy. Finally, there was a strong consensus for the use of telemedicine for monitoring APC patients. PATIENT SUMMARY: In the Advanced Prostate Cancer Consensus Conference 2021, the panellists reached a consensus regarding the recommendation of the COVID-19 vaccine in prostate cancer patients and use of telemedicine for monitoring these patients.
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http://dx.doi.org/10.1016/j.eururo.2022.02.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8849852PMC
February 2022

Testosterone levels and testosterone kinetics: The importance of its clinical significance.

Radiother Oncol 2022 Apr 29;169:148-149. Epub 2022 Jan 29.

Hospital Universitario de La Princesa, Instituto de Investigacion Sanitaria IP, Madrid, Spain. Electronic address:

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http://dx.doi.org/10.1016/j.radonc.2022.01.027DOI Listing
April 2022

Androgen deprivation therapy use and duration with definitive radiotherapy for localised prostate cancer: an individual patient data meta-analysis.

Lancet Oncol 2022 02 17;23(2):304-316. Epub 2022 Jan 17.

Department of Radiation Oncology, University of California Los Angeles, Los Angeles, CA, USA; Department of Urology, University of California Los Angeles, Los Angeles, CA, USA.

Background: Randomised trials have investigated various androgen deprivation therapy (ADT) intensification strategies in men receiving radiotherapy for the treatment of prostate cancer. This individual patient data meta-analysis of relevant randomised trials aimed to quantify the benefit of these interventions in aggregate and in clinically relevant subgroups.

Methods: For this meta-analysis, we performed a systematic literature search in MEDLINE, Embase, trial registries, the Web of Science, Scopus, and conference proceedings to identify trials with results published in English between Jan 1, 1962, and Dec 30, 2020. Multicentre randomised trials were eligible if they evaluated the use or prolongation of ADT (or both) in men with localised prostate cancer receiving definitive radiotherapy, reported or collected distant metastasis and survival data, and used ADT for a protocol-defined finite duration. The Meta-Analysis of Randomized trials in Cancer of the Prostate (MARCAP) Consortium was accessed to obtain individual patient data from randomised trials. The primary outcome was metastasis-free survival. Hazard ratios (HRs) were obtained through stratified Cox models for ADT use (radiotherapy alone vs radiotherapy plus ADT), neoadjuvant ADT extension (ie, extension of total ADT duration in the neoadjuvant setting from 3-4 months to 6-9 months), and adjuvant ADT prolongation (ie, prolongation of total ADT duration in the adjuvant setting from 4-6 months to 18-36 months). Formal interaction tests between interventions and metastasis-free survival were done for prespecified subgroups defined by age, National Comprehensive Cancer Network (NCCN) risk group, and radiotherapy dose. This meta-analysis is registered with PROSPERO, CRD42021236855.

Findings: Our search returned 12 eligible trials that provided individual patient data (10 853 patients) with a median follow-up of 11·4 years (IQR 9·0-15·0). The addition of ADT to radiotherapy significantly improved metastasis-free survival (HR 0·83 [95% CI 0·77-0·89], p<0·0001), as did adjuvant ADT prolongation (0·84 [0·78-0·91], p<0·0001), but neoadjuvant ADT extension did not (0·95 [0·83-1·09], p=0·50). Treatment effects were similar irrespective of radiotherapy dose, patient age, or NCCN risk group.

Interpretation: Our findings provide the strongest level of evidence so far to the magnitude of the benefit of ADT treatment intensification with radiotherapy for men with localised prostate cancer. Adding ADT and prolonging the portion of ADT that follows radiotherapy is associated with improved metastasis-free survival in men, regardless of risk group, age, and radiotherapy dose delivered; however, the magnitude of the benefit could vary and shared decision making with patients is recommended.

Funding: University Hospitals Seidman Cancer Center, Prostate Cancer Foundation, and the American Society for Radiation Oncology.
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http://dx.doi.org/10.1016/S1470-2045(21)00705-1DOI Listing
February 2022

Interplay Between Duration of Androgen Deprivation Therapy and External Beam Radiotherapy With or Without a Brachytherapy Boost for Optimal Treatment of High-risk Prostate Cancer: A Patient-Level Data Analysis of 3 Cohorts.

JAMA Oncol 2022 Mar 17;8(3):e216871. Epub 2022 Mar 17.

Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Importance: Radiotherapy combined with androgen deprivation therapy (ADT) is a standard of care for high-risk prostate cancer. However, the interplay between radiotherapy dose and the required minimum duration of ADT is uncertain.

Objective: To determine the specific ADT duration threshold that provides a distant metastasis-free survival (DMFS) benefit in patients with high-risk prostate cancer receiving external beam radiotherapy (EBRT) or EBRT with a brachytherapy boost (EBRT+BT).

Design, Settings, And Participants: This was a cohort study of 3 cohorts assembled from a multicenter retrospective study (2000-2013); a post hoc analysis of the Randomized Androgen Deprivation and Radiotherapy 03/04 (RADAR; 2003-2007) randomized clinical trial (RCT); and a cross-trial comparison of the RADAR vs the Deprivación Androgénica y Radio Terapía (Androgen Deprivation and Radiation Therapy; DART) 01/05 RCT (2005-2010). In all, the study analyzed 1827 patients treated with EBRT and 1108 patients treated with EBRT+BT from the retrospective cohort; 181 treated with EBRT and 203 with EBRT+BT from RADAR; and 91 patients treated with EBRT from DART. The study was conducted from October 15, 2020, to July 1, 2021, and the data analyses, from January 5 to June 15, 2021.

Exposures: High-dose EBRT or EBRT+BT for an ADT duration determined by patient-physician choice (retrospective) or by randomization (RCTs).

Main Outcomes And Measures: The primary outcome was DMFS; secondary outcome was overall survival (OS). Natural cubic spline analysis identified minimum thresholds (months).

Results: This cohort study of 3 studies totaling 3410 men (mean age [SD], 68 [62-74] years; race and ethnicity not collected) with high-risk prostate cancer found a significant interaction between the treatment type (EBRT vs EBRT+BT) and ADT duration (binned to <6, 6 to <18, and ≥18 months). Natural cubic spline analysis identified minimum duration thresholds of 26.3 months (95% CI, 25.4-36.0 months) for EBRT and 12 months (95% CI, 4.9-36.0 months) for EBRT+BT for optimal effect on DMFS. In RADAR, the prolongation of ADT for patients receiving only EBRT was not associated with significant improvements in DMFS (hazard ratio [HR], 1.01; 95% CI, 0.65-1.57); however, for patients receiving EBRT+BT, a longer duration was associated with improved DMFS (DMFS HR, 0.56; 95% CI, 0.36-0.87; P = .01). For patients receiving EBRT alone (DART), 28 months of ADT was associated with improved DMFS compared with 18 months (RADAR HR, 0.37; 95% CI, 0.17-0.80; P = .01).

Conclusions And Relevance: These cohort study findings suggest that the optimal minimum ADT duration for treatment with high-dose EBRT alone is more than 18 months; and for EBRT+BT, it is 18 months or possibly less. Additional studies are needed to determine more precise minimum durations.
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http://dx.doi.org/10.1001/jamaoncol.2021.6871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8778608PMC
March 2022

Health-related quality of life in men with localized prostate cancer treated with radiotherapy: validation of an abbreviated version of the Expanded Prostate Cancer Index Composite for Clinical Practice in Spain.

Health Qual Life Outcomes 2021 Sep 25;19(1):223. Epub 2021 Sep 25.

Department of Radiation Oncology, ERESA, Hospital General Universitario de València, València, Spain.

Background: Health-related quality of life (HRQoL) is greatly affected by prostate cancer (PCa) and associated treatments. This study aimed to measure the impact of radiotherapy on HRQoL and to further validate the Spanish version of the 16-item Expanded Prostate Cancer Index Composite (EPIC-16) in routine clinical practice.

Methods: An observational, non-interventional, multicenter study was conducted in Spain with localized PCa patients initiating treatment with external beam radiotherapy (EBRT) or brachytherapy (BQT). Changes from baseline in EPIC-16, University of California-Los Angeles Prostate Cancer Index (UCLA-PCI), and patient-perceived health status were longitudinally assessed at end of radiotherapy (V2) and 90 days thereafter (V3). Psychometric evaluations of the Spanish EPIC-16 were conducted.

Results: Of 516 patients enrolled, 495 were included in the analysis (EBRT, n = 361; BQT, n = 134). At baseline, mean (standard deviation [SD]) EPIC-16 global scores were 11.9 (7.5) and 10.3 (7.7) for EBRT and BQT patients, respectively; scores increased, i.e., HRQoL worsened, from baseline, by mean (SD) of 6.8 (7.6) at V2 and 2.4 (7.4) at V3 for EBRT and 4.2 (7.6) and 3.9 (8.2) for BQT patients. Changes in Spanish EPIC-16 domains correlated well with urinary, bowel, and sexual UCLA-PCI domains. EPIC-16 showed good internal consistency (Cronbach's alpha = .84), reliability, and construct validity.

Conclusion: The Spanish EPIC-16 questionnaire demonstrated sensitivity, strong discriminative properties and reliability, and validity for use in clinical practice. EPIC-16 scores worsened after radiotherapy in different HRQoL domains; however, a strong tendency towards recovery was seen at the 3-month follow-up visit.
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http://dx.doi.org/10.1186/s12955-021-01856-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8466718PMC
September 2021

MRI-guided focal boost to dominant intraprostatic lesion using volumetric modulated arc therapy in prostate cancer. Results of a phase II trial.

Br J Radiol 2022 Mar 19;95(1131):20210683. Epub 2021 Sep 19.

Radiation Oncology Department, Hospital Universitario de la Princesa, Health Research Institute IIS-IP, Madrid, Spain.

Objective: To determine morphological and biological control as well as toxicity and quality of life (QoL) of men with localized prostate cancer (PCa) treated with MRI-guided focal boost radiotherapy.

Material And Methods: 30 patients with PCa and a visible dominant intraprostatic lesion (DIL) identified on mpMRI were included in a prospective Phase II trial. Matching point registration of planning CT and T2W, diffusion-weighted and a gradient-recalled echo (GRE) MRI images made in treatment position was used for prostate and tumour delineation. Treatment consisted on 35 daily fractions of 2.17 Gy with a concomitant focal boost to the DIL of 2.43 Gy using volumetric modulated arc therapy (VMAT) and image-guided radiation therapy (IGRT) with intraprostatic fiducial markers. Biochemical failure was analysed using PSA nadir +2 ng/mL criteria and local control using mpMRI evaluation at 6-9 months following RT. Acute and late toxicity were defined according to CTCAE v.4.0 and RTOG/EORTC scales and QoL was assessed using IPSS, EPIC short-form and UCLA-PCI questionnaires.

Results: The median radiation dose to the prostate was 77.6 Gy (IQR 77.3-78.1), and to the DIL was 85.5 Gy (IQR 85.0-86.0). With a median follow up of 30.0 months (IQR 25.5-40.27), all patients remain free of biochemical relapse. An mpMRI complete response was observed in 25 patients during the first post-treatment evaluation at 6 months. The remaining five patients achieved a complete disappearance of the DIL both on T2 and DWI on the second mpMRI performed at 9 months following treatment. Six out of 30 (20%) patients presented acute Grade 2 urinary toxicity with no Grade 3 acute complications. Acute rectal toxicity was only found in 2 (6.6%) patients (both Grade 1). Only late Grade 1 urinary and rectal complications were observed in 3/30 patients, respectively, with no Grade 2 or more late toxicity. The urinary, bowel and sexual bother EPIC scores were slightly and insignificantly increased in the first 3 months post-treatment, returning to normal afterwards.

Conclusions: mpMRI-guided focal boost using VMAT hypofractionated technique is associated with an excellent morphological and functional response control and a safe toxicity profile.

Advances In Knowledge: In the present trial, we examined the potential role of mpMRI for radiological assessment (functional and morphological) of treatment response in high-risk prostate cancer patients treated with MRI-guided focal radiotherapy dose intensification to dominant Intraprostatic lesion.
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http://dx.doi.org/10.1259/bjr.20210683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8978233PMC
March 2022

Prognostic value of testosterone castration levels following androgen deprivation and high-dose radiotherapy in localized prostate cancer: Results from a phase III trial.

Radiother Oncol 2021 07 5;160:115-119. Epub 2021 May 5.

Hospital General Universitario Gregorio Marañón, Madrid, Spain.

Background/objective: The optimal prognostic value of testosterone following androgen deprivation therapy (ADT) is controversial. We studied the effect of serum testosterone levels on clinical outcome in localized prostate cancer (PCa) treated with ADT and high-dose radiotherapy (HRT).

Patients And Methods: The DART01/05 trial randomized 355 men with intermediate and high-risk PCa to 4 months of ADT plus HRT (STADT, N = 178) or the same treatment followed by 24 months of ADT (LTADT, N = 177). This study included patients treated with LTADT who had at least 3 determinations of testosterone during ADT (N = 154). Patients were stratified into 3 subgroups by testosterone level: minimum <20 ng/dL; median 20-49 ng/dL; and maximum ≥50 ng/dL. Kaplan-Meyer and Cox regression analysis were used for overall survival (OS) and Fine & Gray regression model for metastasis free survival (MFS), biochemical disease-free survival (bDFS) and time to TT recovery.

Results: There were no statistically significant differences in 10-year bDFS, MFS, or OS between the <20 ng/mL and 20-49 ng/dL subgroups. Multivariate analysis showed that a median testosterone ≥50 ng/dL was significantly associated with a decrease in bDFS (HR: 6.58, 95%CI 1.28-33.76, p = 0.03). Time to testosterone recovery after ADT did not correlate with bDFS, MFS, or OS and was not significantly associated with any of the testosterone subgroups.

Conclusions: Our results do not support the concept that additional serum testosterone suppression below 20 ng/dL is associated with better outcomes than 20-49 ng/dL. Time to testosterone recovery after ADT and HRT did not impact clinical failure.
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http://dx.doi.org/10.1016/j.radonc.2021.04.018DOI Listing
July 2021

The Multicenter, Randomized, Phase 2 PEACE V-STORM Trial: Defining the Best Salvage Treatment for Oligorecurrent Nodal Prostate Cancer Metastases.

Eur Urol Focus 2021 03 29;7(2):241-244. Epub 2020 Dec 29.

Department of Radiation Oncology and Experimental Cancer Research, Ghent University Hospital, Ghent, Belgium. Electronic address:

Optimal local treatment for nodal oligorecurrent prostate cancer is unknown. The randomized phase 2 PEACE V-STORM trial will explore the best treatment approach in this setting. Early results on the acute toxicity profile are projected to be published in quarter 3, 2021.
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http://dx.doi.org/10.1016/j.euf.2020.12.010DOI Listing
March 2021

Detection and dynamics of circulating tumor cells in patients with high-risk prostate cancer treated with radiotherapy and hormones: a prospective phase II study.

Radiat Oncol 2020 Jun 1;15(1):137. Epub 2020 Jun 1.

Methodology Unit, Health Research Institute of Hospital Universitario de La Princesa, Madrid, Spain.

Background: Circulating tumor cells (CTCs) are an established prognostic marker in castration-resistant prostate cancer but have received little attention in localized high-risk disease. We studied the detection rate of CTCs in patients with high-risk prostate cancer before and after androgen deprivation therapy and radiotherapy to assess its value as a prognostic and monitoring marker.

Patients And Methods: We performed a prospective analysis of CTCs in the peripheral blood of 65 treatment-naïve patients with high-risk prostate cancer. EpCAM-positive CTCs were enumerated using the CELLSEARCH system at 4 timepoints. A cut off of 0 vs ≥ 1 CTC/7.5 ml blood was defined as a threshold for negative versus positive CTCs status.

Results: CTCs were detected in 5/65 patients (7.5%) at diagnosis, 8/62 (12.9%) following neoadjuvant androgen deprivation and 11/59 (18.6%) at the end of radiotherapy, with a median CTC count/7.5 ml of 1 (range, 1-136). Only 1 patient presented a positive CTC result 9 months after radiotherapy. Positive CTC status (at any timepoint) was not significantly associated with any clinical or pathologic factors. However, when we analyzed variations in CTC patterns following treatment, we observed a significant association between conversion of CTCs and stages T3 (P = 0.044) and N1 (P = 0.002). Detection of CTCs was not significantly associated with overall survival (P > 0.40).

Conclusions: Our study showed a low detection rate for CTCs in patients with locally advanced high-risk prostate cancer. The finding of a de novo positive CTC count after androgen deprivation therapy is probably due to a passive mechanism associated with the destruction of the tumor. Further studies with larger samples and based on more accurate detection of CTCs are needed to determine the potential prognostic and therapeutic value of this approach in non-metastatic prostate cancer.

Trial Registration: ClinicalTrials.gov ID: NCT01800058.
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http://dx.doi.org/10.1186/s13014-020-01577-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268302PMC
June 2020

Management of Patients with Advanced Prostate Cancer: Report of the Advanced Prostate Cancer Consensus Conference 2019.

Eur Urol 2020 04 27;77(4):508-547. Epub 2020 Jan 27.

Division of Medical Oncology, National Cancer Centre, Singapore.

Background: Innovations in treatments, imaging, and molecular characterisation in advanced prostate cancer have improved outcomes, but there are still many aspects of management that lack high-level evidence to inform clinical practice. The Advanced Prostate Cancer Consensus Conference (APCCC) 2019 addressed some of these topics to supplement guidelines that are based on level 1 evidence.

Objective: To present the results from the APCCC 2019.

Design, Setting, And Participants: Similar to prior conferences, experts identified 10 important areas of controversy regarding the management of advanced prostate cancer: locally advanced disease, biochemical recurrence after local therapy, treating the primary tumour in the metastatic setting, metastatic hormone-sensitive/naïve prostate cancer, nonmetastatic castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, bone health and bone metastases, molecular characterisation of tissue and blood, inter- and intrapatient heterogeneity, and adverse effects of hormonal therapy and their management. A panel of 72 international prostate cancer experts developed the programme and the consensus questions.

Outcome Measurements And Statistical Analysis: The panel voted publicly but anonymously on 123 predefined questions, which were developed by both voting and nonvoting panel members prior to the conference following a modified Delphi process.

Results And Limitations: Panellists voted based on their opinions rather than a standard literature review or formal meta-analysis. The answer options for the consensus questions had varying degrees of support by the panel, as reflected in this article and the detailed voting results reported in the Supplementary material.

Conclusions: These voting results from a panel of prostate cancer experts can help clinicians and patients navigate controversial areas of advanced prostate management for which high-level evidence is sparse. However, diagnostic and treatment decisions should always be individualised based on patient-specific factors, such as disease extent and location, prior lines of therapy, comorbidities, and treatment preferences, together with current and emerging clinical evidence and logistic and economic constraints. Clinical trial enrolment for men with advanced prostate cancer should be strongly encouraged. Importantly, APCCC 2019 once again identified important questions that merit assessment in specifically designed trials.

Patient Summary: The Advanced Prostate Cancer Consensus Conference provides a forum to discuss and debate current diagnostic and treatment options for patients with advanced prostate cancer. The conference, which has been held three times since 2015, aims to share the knowledge of world experts in prostate cancer management with health care providers worldwide. At the end of the conference, an expert panel discusses and votes on predefined consensus questions that target the most clinically relevant areas of advanced prostate cancer treatment. The results of the voting provide a practical guide to help clinicians discuss therapeutic options with patients as part of shared and multidisciplinary decision making.
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http://dx.doi.org/10.1016/j.eururo.2020.01.012DOI Listing
April 2020

Salvage brachytherapy for locally-recurrent prostate cancer after radiation therapy: A comparison of efficacy and toxicity outcomes with high-dose rate and low-dose rate brachytherapy.

Radiother Oncol 2019 12 27;141:156-163. Epub 2019 Sep 27.

Computing Services, Research Support, Complutense University of Madrid, Spain. Electronic address:

Background: Brachytherapy (BT) is widely used for salvage therapy in patients with biochemical failure (BF) after radiotherapy for prostate cancer (PCa). Although low-dose-rate (LDR) and high-dose-rate (HDR) BT are both used for salvage therapy, it is not clear whether there are any differences between these two approaches in terms of efficacy or toxicity in this setting. Therefore, we review the institutional experience of the members of the Urological Tumour Working Group (URONCOR) of the Spanish Society of Radiation Oncology (SEOR) to compare these two techniques.

Methods And Materials: Between 2001 and 2016, 119 patients with biopsy-proven, locally-recurrent PCa underwent salvage BT (LDR, n = 44; HDR, n = 75) after primary radiotherapy. Relapse-free survival (RFS) and cause-specific survival (CSS) after salvage therapy were analyzed. Toxicity was assessed according to the RTOG scale.

Results: Median follow-up after salvage BT was 52 months. Overall, the 5-year prostate-specific antigen (PSA) RFS rate was 71% (95% CI, 65.9%-75.9%). No significant between-group differences in RFS were observed (p = 0.063). Five-year CSS for the LDR- and HDR-BT groups were 96.5% and 93%, respectively. Overall, 38 patients (32%) developed biochemical progression (Phoenix definition) after salvage BT: 14 patients (32%) in the LDR group and 24 (32.5%) in the HDR group. On the multivariate analysis, the following variables were significantly associated with progression, time to BF from primary radiotherapy <30 months (p = 0.014); and post-salvage nadir PSA (p = 0.000). There were no significant between-group differences in toxicity. Overall, there were 13 cases of urethral stricture, 22 cases of urinary incontinence, and 13 cases of haematuria. Toxicity ≥grade 3 was observed in 23.5% of patients.

Conclusions: These findings show that both HDR-BT and LDR-BT yield comparable efficacy and toxicity outcomes in patients undergoing salvage treatment for locally-recurrent prostate cancer after primary radiotherapy. Predictors of worse outcomes after salvage BT were post-salvage nadir PSA and time to BF from initial radiotherapy.
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http://dx.doi.org/10.1016/j.radonc.2019.09.006DOI Listing
December 2019

Long-term Outcomes and Patterns of Failure Following Trimodality Treatment With Bladder Preservation for Invasive Bladder Cancer.

Urology 2019 Feb 25;124:183-190. Epub 2018 Sep 25.

Department of Radiation Oncology, Hospital Universitario de La Princesa, Madrid, Spain.

Objective: To report long-term results on survival, toxicity, and patterns of failure of 3 different organ-sparing strategies for patients with muscle invasive bladder cancer.

Materials And Methods: This is a monoinstitutional prospective analysis of 3 consecutive bladder-sparing protocols combining maximal transurethral resection of bladder tumor (mTURBT), radiotherapy (RT), and cisplatin-based chemotherapy. Protocol 1 consisted of neoadjuvant methotrexate-cisplatin-vinblastine followed by endoscopic re-evaluation and consolidative RT 60 Gy in complete responders. Protocol 2 involved altered-fractionation RT 64.8 Gy and concurrent weekly cisplatin with re-evaluation after 40.8 Gy. Protocol 3 consisted of RT 64.8 Gy with concomitant weekly cisplatin. Nonresponders underwent radical cystectomy. Probabilities for overall survival (OS), cancer-specific survival (CSS), and metastasis-free survival (MFS) were calculated using Kaplan-Meier product limited estimates. A Cox regression multivariate analysis was performed to detect potential risk factors for OS, CSS, and MFS.

Results: The 10-year bladder preservation rate was 79%. The 10-year OS, CSS, and MFS rates were 43.2%, 76.3% and 79.2%, respectively. There was no statistically significant difference in OS between the different treatment protocols. On multivariate analysis, mTURBT of the bladder and the complete response after induction therapy were independent correlates of improved OS and of MFS. The development of invasive bladder recurrence was independently associated with worse CSS and MFS.

Conclusion: Ten-year results indicate that bladder-sparing treatment is a successful approach for muscle invasive bladder cancer in selected patients. The mTURBT of the bladder tumor and complete response after induction therapy remain the most relevant predictive factors.
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http://dx.doi.org/10.1016/j.urology.2018.07.058DOI Listing
February 2019

Late Radiation and Cardiovascular Adverse Effects After Androgen Deprivation and High-Dose Radiation Therapy in Prostate Cancer: Results From the DART 01/05 Randomized Phase 3 Trial.

Int J Radiat Oncol Biol Phys 2016 10 22;96(2):341-348. Epub 2016 Jun 22.

Hospital General Universitario Gregorio Marañón, Madrid, Spain.

Purpose: To present data on the late toxicity endpoints of a randomized trial (DART 01/05) conducted to determine whether long-term androgen deprivation (LTAD) was superior to short-term AD (STAD) when combined with high-dose radiation therapy (HDRT) in patients with prostate cancer (PCa).

Patients And Methods: Between November 2005 and December 2010, 355 eligible men with cT1c-T3aN0M0 PCa and intermediate-risk and high-risk factors (2005 National Comprehensive Cancer Network criteria) were randomized to 4 months of AD combined with HDRT (median dose, 78 Gy) (STAD) or the same treatment followed by 24 months of AD (LTAD). Treatment-related complications were assessed using European Organization for Research and Treatment of Cancer-Radiation Therapy Oncology Group and Common Terminology Criteria for Adverse Events v3.0 scoring schemes. Multivariate analyses for late toxicity were done using the Fine-Gray method.

Results: The 5-year incidence of grade ≥2 rectal and urinary toxicity was 11.1% and 8.2% for LTAD and 7.6% and 7.3% for STAD, respectively. Compared with STAD, LTAD was not significantly associated with a higher risk of late grade ≥2 rectal toxicity (hazard ratio [HR] 1.360, 95% confidence interval [CI] 0.660-2.790, P=.410) or urinary toxicity (HR 1.028, 95% CI 0.495-2.130, P=.940). The multivariate analysis showed that a baseline history of intestinal comorbidity (HR 3.510, 95% CI 1.560-7.930, P=.025) and the rectal volume receiving >60 Gy (Vr60) (HR 1.030, 95% CI 1.001-1.060, P=.043) were the only factors significantly correlated with the risk of late grade ≥2 rectal complications. A history of previous surgical prostate manipulations was significantly associated with a higher risk of grade ≥2 urinary complications (HR 2.427, 95% CI 1.051-5.600, P=.038). Long-term AD (HR 2.090; 95% CI 1.170-3.720, P=.012) and a history of myocardial infarction (HR 2.080; 95% CI 1.130-3.810, P=.018) were significantly correlated with a higher probability of cardiovascular events.

Conclusion: Long-term AD did not significantly impact urinary or rectal radiation-induced toxicity, although it was associated with a higher risk of cardiovascular events. Longer follow-up is needed to measure the impact of AD on late morbidity and non-PCa mortality.
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http://dx.doi.org/10.1016/j.ijrobp.2016.06.2445DOI Listing
October 2016

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

Strahlenther Onkol 2015 Oct 9;191(10):792-800. Epub 2015 Jul 9.

Departamento de Métodos Estadísticos, Universidad de Zaragoza, Zaragoza, Spain.

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.
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http://dx.doi.org/10.1007/s00066-015-0866-7DOI Listing
October 2015

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

Rep Pract Oncol Radiother 2015 Jul-Aug;20(4):259-72. Epub 2015 May 30.

Servicio de Oncología Radioterápica, Hospital Universitario Gregorio Marañón, Madrid, Spain.

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.
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http://dx.doi.org/10.1016/j.rpor.2015.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4477122PMC
June 2015

Reporting of results in DART01/05 GICOR - Author's reply.

Lancet Oncol 2015 Jun 27;16(6):e258-9. Epub 2015 May 27.

Radiation Oncology Department, Hospital Universitario de la Princesa, Health Research Institute IIS, 28006 Madrid, Spain. Electronic address:

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http://dx.doi.org/10.1016/S1470-2045(15)70245-7DOI Listing
June 2015

High-dose radiotherapy with short-term or long-term androgen deprivation in localised prostate cancer (DART01/05 GICOR): a randomised, controlled, phase 3 trial.

Lancet Oncol 2015 Mar 19;16(3):320-7. Epub 2015 Feb 19.

Hospital General Universitario Gregorio Marañón, Madrid, Spain.

Background: The optimum duration of androgen deprivation combined with high-dose radiotherapy in prostate cancer remains undefined. We aimed to determine whether long-term androgen deprivation was superior to short-term androgen deprivation when combined with high-dose radiotherapy.

Methods: In this open-label, multicentre, phase 3 randomised controlled trial, patients were recruited from ten university hospitals throughout Spain. Eligible patients had clinical stage T1c-T3b N0M0 prostate adenocarcinoma with intermediate-risk and high-risk factors according to 2005 National Comprehensive Cancer Network criteria. Patients were randomly assigned (1:1) using a computer-generated randomisation schedule to receive either 4 months of androgen deprivation combined with three-dimensional conformal radiotherapy at a minimum dose of 76 Gy (range 76-82 Gy; short-term androgen deprivation group) or the same treatment followed by 24 months of adjuvant androgen deprivation (long-term androgen deprivation group), stratified by prostate cancer risk group (intermediate risk vs high risk) and participating centre. Patients assigned to the short-term androgen deprivation group received 4 months of neoadjuvant and concomitant androgen deprivation with subcutaneous goserelin (2 months before and 2 months combined with high-dose radiotherapy). Anti-androgen therapy (flutamide 750 mg per day or bicalutamide 50 mg per day) was added during the first 2 months of treatment. Patients assigned to long-term suppression continued with the same luteinising hormone-releasing hormone analogue every 3 months for another 24 months. The primary endpoint was biochemical disease-free survival. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT02175212.

Findings: Between Nov 7, 2005, and Dec 20, 2010, 178 patients were randomly assigned to receive short-term androgen deprivation and 177 to receive long-term androgen deprivation. After a median follow-up of 63 months (IQR 50-82), 5-year biochemical disease-free survival was significantly better among patients receiving long-term androgen deprivation than among those receiving short-term treatment (90% [95% CI 87-92] vs 81% [78-85]; hazard ratio [HR] 1·88 [95% CI 1·12-3·15]; p=0·01). 5-year overall survival (95% [95% CI 93-97] vs 86% [83-89]; HR 2·48 [95% CI 1·31-4·68]; p=0·009) and 5-year metastasis-free survival (94% [95% CI 92-96] vs 83% [80-86]; HR 2·31 [95% CI 1·23-3·85]; p=0·01) were also significantly better in the long-term androgen deprivation group than in the short-term androgen deprivation group. The effect of long-term androgen deprivation on biochemical disease-free survival, metastasis-free survival, and overall survival was more evident in patients with high-risk disease than in those with low-risk disease. Grade 3 late rectal toxicity was noted in three (2%) of 177 patients in the long-term androgen deprivation group and two (1%) of 178 in the short-term androgen deprivation group; grade 3-4 late urinary toxicity was noted in five (3%) patients in each group. No deaths related to treatment were reported.

Interpretation: Compared with short-term androgen deprivation, 2 years of adjuvant androgen deprivation combined with high-dose radiotherapy improved biochemical control and overall survival in patients with prostate cancer, particularly those with high-risk disease, with no increase in late radiation toxicity. Longer follow-up is needed to determine whether men with intermediate-risk disease benefit from more than 4 months of androgen deprivation.

Funding: Spanish National Health Investigation Fund, AstraZeneca.
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http://dx.doi.org/10.1016/S1470-2045(15)70045-8DOI Listing
March 2015

HIF1A expression in localized prostate cancer treated with dose escalation radiation therapy.

Cancer Biomark 2015 ;15(1):41-6

Department of Radiation Oncology, La Princesa University Hospital, Madrid, Spain.

Purpose: To analyze the expression of hypoxia inducible factor 1 alpha (HIF1A) and its correlation with clinical outcome in men with localized prostate cancer (PC) treated with dose escalation radiotherapy (RT) and androgen deprivation (AD).

Methods: Between 1996 and 2004, 129 PC patients who had diagnostic biopsies pre-treatment and 24-36 months following RT were enrolled in this study. Median follow-up was 129 months. Suitable archival diagnostic tissue was obtained from 86 patients. Correlation analysis was done to assess association between HIF1A expression and clinical outcome.

Results: HIF1A expression was observed in 25/86 (29%) of diagnostic biopsies, and in 5/14 (36%) of post-RT biopsies. No significant association was noted between HIF1A expression and clinical and treatment parameters. We also failed to show a significant correlation between HIF1A overexpression and outcome. A borderline significant relationship was observed between expression of HIF1A and overall survival (OS) (HR 0.03, p=0.08).

Conclusion: To our knowledge this is the first study assessing the pattern of change of HIF1A staining in biopsies of patients prior and following treatment. While we did not find significant variations in the expression of HIF1A following radio-hormone therapy, a high HIF1A expression was unexpectedly associated with a borderline improved OS.
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http://dx.doi.org/10.3233/CBM-140439DOI Listing
August 2015

Predictive value of PAK6 and PSMB4 expression in patients with localized prostate cancer treated with dose-escalation radiation therapy and androgen deprivation therapy.

Urol Oncol 2014 Nov 16;32(8):1327-32. Epub 2014 Jun 16.

Department of Radiation Oncology, La Princesa University Hospital, Madrid, Spain.

Purpose: The present study analyzed the expression by immunochemistry of the novel markers P21-activated protein kinase 6 (PAK6) and proteasome beta-4 subunit (PSMB4) in men with localized prostate cancer (PC) who were treated with dose-escalation radiotherapy (RT) and androgen deprivation therapy.

Materials And Methods: Between 1996 and 2004, a cohort of 129 patients with PC who underwent diagnostic biopsies pretreatment and 24 to 36 months following RT were enrolled in this study. Suitable archival diagnostic tissue was obtained from 89 patients. Median follow-up was 129 months (48-198). Correlation analysis was done to assess association between PAK6 and PSMB4 expression and clinical outcome.

Results: PAK6 and PSMB4 were expressed in the cytoplasm in 62% and 96.7% of diagnostic biopsies, respectively. Increased staining for PAK6 was significantly (P = 0.04) correlated with higher Gleason scores. In the multivariate analysis, the intensity of PSMB4 staining was an independent predictor of local relapse (hazard ratio = 8.6, P = 0.04).

Conclusions: To our knowledge, this is the first description of PAK6 and PSMB4 expression in the diagnostic specimens of men with PC who were treated with RT. If confirmed by further studies, increased expression of these genes could be used to identify patients at a high risk of developing local failure following high-dose RT, thus better tailoring treatments for the individual patient.
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http://dx.doi.org/10.1016/j.urolonc.2014.05.004DOI Listing
November 2014

Long-term results of two prospective bladder-sparing trimodality approaches for invasive bladder cancer: neoadjuvant chemotherapy and concurrent radio-chemotherapy.

Urology 2012 Nov 19;80(5):1056-62. Epub 2012 Sep 19.

Department of Radiation Oncology Hospital Universitario de la Princesa, Instituto Investigación Sanitaria IP, Madrid, Spain.

Objective: To report long-term outcomes of selective organ preservation for muscle-invasive bladder cancer (MIBC) using 2 bladder-sparing trimodality approaches.

Materials And Methods: From 1990 to 2010, 80 patients with T2-T4 bladder cancer were prospectively enrolled in 2 successive bladder-sparing protocols. Forty-one patients were treated with neoadjuvant methotrexate, cisplatin, and vinblastine (MCV) chemotherapy followed by radiotherapy (60 Gy) in complete responders (protocol 1 [P1]) and 39 patients were treated with weekly cisplatin concurrent with radiotherapy (64.8 Gy) (protocol 2 [P2]).

Results: The median follow-up was 72 months (range, 9-204 months). Five and 10-year cumulative overall survival for all series were 73% and 60% and the corresponding numbers for cancer-specific survival were 82% and 80%, respectively. Of all surviving patients, 83% maintained their own bladder. Although there were no significant differences in overall survival (P = .820), cancer-specific survival (P = .688) and distant metastasis (P = .417) between protocols, complete response rates (P = .003), and disease-free survival (P = .031) were significantly higher in P2 treatment.

Conclusion: Trimodality therapy with bladder preservation represents a real alternative to radical cystectomy (RC) in selected patients. Overall survival and cancer-specific survival rates are encouraging with more than 80% of survivors retaining functional bladders.
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http://dx.doi.org/10.1016/j.urology.2012.07.045DOI Listing
November 2012

Practice patterns in the management of prostate cancer in Spain: results from a national survey among radiation oncologists in 2009.

Clin Transl Oncol 2013 Mar 2;15(3):226-32. Epub 2012 Aug 2.

Department of Radiation Oncology, Health Research Institute IP, Hospital Universitario de la Princesa, Diego de León, 62, 28006, Madrid, Spain.

Introduction: Little is known of practice patterns on advanced prostate cancer (PC) in Spain. The study objectives were to investigate practice patterns in the management of PC and to determine the adherence to the 2007 Spanish guidelines for the management of PC.

Materials And Methods: An epidemiological, cross-sectional study was undertaken. Study-specific questionnaires were distributed to all centers with radiation oncology (RO) facilities delivering megavoltage radiation therapy (RT) in Spain (n = 108). A questionnaire evaluated diagnostic and treatment approaches to PC in low-risk and high-risk cases. And a 12-item questionnaire was used to assess guidelines adherence.

Results: Responses were obtained from 102 centers (94.0 % response rate). In the high-risk scenario, the majority of clinicians (99.0 %) chose combined modality treatment with RT and androgen deprivation (AD) and 93.0 % recommended long-term AD. External-beam RT (EBRT) doses ranging 72-76 Gy were used in 59.5 % of centers and >76 Gy was employed in 40.5 %. In the low-risk scenario, EBRT was chosen by 59.6 %, brachytherapy by 39.4 %, and active surveillance by 1 %. The consensus was high (score 5 + 4 ≥ 90 %) on 8/12 questions assessing adherence to guidelines, being high specifically on items related to RT technique, RT dose, combination of HT and RT in intermediate/high-risk patients, and prognostic factors.

Conclusions: This is the largest survey to date of Spanish RO departments dealing with PC. The study results therefore likely provide a highly reliable picture of clinical practice in Spain in this century and show how this practice is influenced by clinical evidence from randomized trials and consensus conferences.
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http://dx.doi.org/10.1007/s12094-012-0913-0DOI Listing
March 2013

[Molecular markers as predictive factors biochemical failure after radical treatment of prostate cancer].

Arch Esp Urol 2012 Jan-Feb;65(1):61-78

Servicio de Oncología Radioterápica, Hospital Universitario de la Princesa, Madrid, España.

Clinical nomograms based on Gleason grade, tumor stage, and serum PSA are still the best predictors of prostate cancer (PC) outcome. The biotechnological advancements achieved in the last decade represent a remarkable source for new prognostic and predictive tissue and serum molecular biomarkers. In this review, we will summarize conventional PC prognostic biomarkers and focus on novel identified biomarkers for PC early diagnosis and progression that might be used in the future. Although they are not ready for widespread, routine use, there are reasons to believe that future models will combine these markers with traditional pretreatment and treatment-related variables and will improve our ability to predict outcome and select the optimal treatment.
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June 2012

Sensitivity of a helical diode array device to delivery errors in IMRT treatment and establishment of tolerance level for pretreatment QA.

J Appl Clin Med Phys 2012 Jan 5;13(1):3660. Epub 2012 Jan 5.

Department of Radiation Oncology and Medical Physics, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria la Princesa, Madrid 28006, Spain.

The aim of this study is to determine the gantry angle and multileaf collimator (MLC) gap error-detection threshold of a diode helical array with an inserted micro-ionization chamber in order to use this device for the pretreatment quality assurance (QA) of intensity-modulated radiation therapy (IMRT) treatments. Implications on the dose-volume histograms (DVHs) of the patient treatments will also be considered for the establishment of a QA protocol with a reasonable tolerance level. Three dynamic IMRT HN (head and neck) and prostate treatments were studied. Random and systematic variations of gantry angle and systematic errors in MLC gap width of the clinical treatments were analyzed in order to establish the detection sensitivity of the array. The associated clinical significance was studied introducing the same errors in the treatment plan based on the patients' computed tomography (CT) and calculating the corresponding DVHs. The Gamma (3%/3 mm) presented a 4% variation in failure rate for a rotation error of 1° for both types of treatment. Both systematic and random errors in gantry rotation angle have little effect on the patients' DVHs. MLC gap width errors of 1 mm and 2 mm in the prostate treatments imply a mean variation in isocenter-measured absorbed dose of 2.1% and 4.1%, respectively. In the case of HN, these errors entail a change in measured isocenter dose of 4.7% and 8.6%, respectively. The variation observed in the DVHs of the patients was, basically, a global displacement of the curves proportional to the isocenter dose variation caused by the gap width error. According to the array sensitivity to the analyzed errors and its implication in patient DVHs, a tolerance of 95% point passing rate for the gamma criterion 3%/2 mm and an agreement of 2% in isocenter absolute dose have been established as tolerance criteria for our pretreatment IMRT QA protocol.
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http://dx.doi.org/10.1120/jacmp.v13i1.3660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5716126PMC
January 2012

Long-term results after high-dose radiotherapy and adjuvant hormones in prostate cancer: how curable is high-risk disease?

Int J Radiat Oncol Biol Phys 2011 Dec 6;81(5):1279-85. Epub 2010 Oct 6.

Department of Radiation Oncology, Hospital Universitario de la Princesa, Madrid, Spain.

Purpose: To analyze long-term outcome and prognostic factors for high-risk prostate cancer defined by National Comprehensive Cancer Network criteria treated with high-dose radiotherapy and androgen deprivation in a single institution.

Methods And Materials: A total of 306 patients treated between 1995 and 2007 in a radiation dose-escalation program fulfilled the National Comprehensive Cancer Network high-risk criteria. Median International Commission on Radiation Units and Measurements radiation dose was 78 Gy (range, 66.0-84.1 Gy). Long-term androgen deprivation (LTAD) was administered in 231 patients, short-term androgen deprivation (STAD) in 59 patients, and no hormones in 16 patients. The Phoenix (nadir plus 2 ng/mL) consensus definition was used for biochemical control. Multivariate analysis was performed to determine the independent prognostic impact of clinical and treatment factors. Median follow-up time was 64 months (range, 24-171 months).

Results: The actuarial overall survival at 5 and 10 years was 95.7% and 89.8%, respectively, and the corresponding biochemical disease-free survival (bDFS) was 89.5% and 67.2%, respectively. Fourteen patients (4.6%) developed distant metastasis. Multivariate analysis showed that Gleason score>7 (p=0.001), pretreatment prostate-specific antigen (PSA) level>20 ng/mL (p=0.037), higher radiation dose (p=0.005), and the use of adjuvant LTAD vs. STAD (p=0.011) were independent prognostic factors affecting bDFS in high-risk disease. The 5-year bDFS for patients treated with LTAD plus radiotherapy dose>78 Gy was 97%.

Conclusions: For high-risk patients the present series showed that the use of LTAD in conjunction with higher doses (>78 Gy) of radiotherapy was associated with improved biochemical tumor control. We observed that the presence of Gleason sum>7 and pretreatment PSA level>20 ng/mL in the same patient represents a 6.8 times higher risk of PSA failure. These men could be considered for clinical trials with addition of novel agents.
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http://dx.doi.org/10.1016/j.ijrobp.2010.07.1975DOI Listing
December 2011
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