Publications by authors named "Rafael Martinez-Monge"

80 Publications

Comparison of Multimodal Therapies and Outcomes Among Patients With High-Risk Prostate Cancer With Adverse Clinicopathologic Features.

JAMA Netw Open 2021 Jul 1;4(7):e2115312. Epub 2021 Jul 1.

Department of Urology, Brady Urological Institute, Johns Hopkins University, Baltimore, Maryland.

Importance: The optimal management strategy for high-risk prostate cancer and additional adverse clinicopathologic features remains unknown.

Objective: To compare clinical outcomes among patients with high-risk prostate cancer after definitive treatment.

Design, Setting, And Participants: This retrospective cohort study included patients with high-risk prostate cancer (as defined by the National Comprehensive Cancer Network [NCCN]) and at least 1 adverse clinicopathologic feature (defined as any primary Gleason pattern 5 on biopsy, clinical T3b-4 disease, ≥50% cores with biopsy results positive for prostate cancer, or NCCN ≥2 high-risk features) treated between 2000 and 2014 at 16 tertiary centers. Data were analyzed in November 2020.

Exposures: Radical prostatectomy (RP), external beam radiotherapy (EBRT) with androgen deprivation therapy (ADT), or EBRT plus brachytherapy boost (BT) with ADT. Guideline-concordant multimodal treatment was defined as RP with appropriate use of multimodal therapy (optimal RP), EBRT with at least 2 years of ADT (optimal EBRT), or EBRT with BT with at least 1 year ADT (optimal EBRT with BT).

Main Outcomes And Measures: The primary outcome was prostate cancer-specific mortality; distant metastasis was a secondary outcome. Differences were evaluated using inverse probability of treatment weight-adjusted Fine-Gray competing risk regression models.

Results: A total of 6004 men (median [interquartile range] age, 66.4 [60.9-71.8] years) with high-risk prostate cancer were analyzed, including 3175 patients (52.9%) who underwent RP, 1830 patients (30.5%) who underwent EBRT alone, and 999 patients (16.6%) who underwent EBRT with BT. Compared with RP, treatment with EBRT with BT (subdistribution hazard ratio [sHR] 0.78, [95% CI, 0.63-0.97]; P = .03) or with EBRT alone (sHR, 0.70 [95% CI, 0.53-0.92]; P = .01) was associated with significantly improved prostate cancer-specific mortality; there was no difference in prostate cancer-specific mortality between EBRT with BT and EBRT alone (sHR, 0.89 [95% CI, 0.67-1.18]; P = .43). No significant differences in prostate cancer-specific mortality were found across treatment cohorts among 2940 patients who received guideline-concordant multimodality treatment (eg, optimal EBRT alone vs optimal RP: sHR, 0.76 [95% CI, 0.52-1.09]; P = .14). However, treatment with EBRT alone or EBRT with BT was consistently associated with lower rates of distant metastasis compared with treatment with RP (eg, EBRT vs RP: sHR, 0.50 [95% CI, 0.44-0.58]; P < .001).

Conclusions And Relevance: These findings suggest that among patients with high-risk prostate cancer and additional unfavorable clinicopathologic features receiving guideline-concordant multimodal therapy, prostate cancer-specific mortality outcomes were equivalent among those treated with RP, EBRT, and EBRT with BT, although distant metastasis outcomes were more favorable among patients treated with EBRT and EBRT with BT. Optimal multimodality treatment is critical for improving outcomes in patients with high-risk prostate cancer.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.15312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251338PMC
July 2021

Patterns of Clinical Progression in Radiorecurrent High-risk Prostate Cancer.

Eur Urol 2021 Aug 10;80(2):142-146. Epub 2021 May 10.

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

The natural history of radiorecurrent high-risk prostate cancer (HRPCa) is not well-described. To better understand its clinical course, we evaluated rates of distant metastases (DM) and prostate cancer-specific mortality (PCSM) in a cohort of 978 men with radiorecurrent HRPCa who previously received either external beam radiation therapy (EBRT, n = 654, 67%) or EBRT + brachytherapy (EBRT + BT, n = 324, 33%) across 15 institutions from 1997 to 2015. In men who did not die, median follow-up after treatment was 8.9 yr and median follow-up after biochemical recurrence (BCR) was 3.7 yr. Local and systemic therapy salvage, respectively, were delivered to 21 and 390 men after EBRT, and eight and 103 men after EBRT + BT. Overall, 435 men developed DM, and 248 were detected within 1 yr of BCR. Measured from time of recurrence, 5-yr DM rates were 50% and 34% after EBRT and EBRT + BT, respectively. Measured from BCR, 5-yr PCSM rates were 27% and 29%, respectively. Interval to BCR was independently associated with DM (p < 0.001) and PCSM (p < 0.001). These data suggest that radiorecurrent HRPCa has an aggressive natural history and that DM is clinically evident early after BCR. These findings underscore the importance of further investigations into upfront risk assessment and prompt systemic evaluation upon recurrence in HRPCa. PATIENT SUMMARY: High-risk prostate cancer that recurs after radiation therapy is an aggressive disease entity and spreads to other parts of the body (metastases). Some 60% of metastases occur within 1 yr. Approximately 30% of these patients die from their prostate cancer.
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http://dx.doi.org/10.1016/j.eururo.2021.04.035DOI Listing
August 2021

Minimally invasive tumor bed implant (MITBI) and peri-operative high-dose-rate brachytherapy (PHDRBT) for accelerated minimal breast irradiation (AMBI) or anticipated boost (A-PHDRBT-boost) in breast-conserving surgery for ductal carcinoma in situ.

J Contemp Brachytherapy 2020 Dec 16;12(6):521-532. Epub 2020 Dec 16.

Department of Oncology, University of Navarra, Pamplona-Madrid, Spain.

Purpose: To evaluate our institutional experience of minimally invasive tumor bed implantation (MITBI) during breast-conserving surgery (BCS) for ductal carcinoma (DCIS) to deliver peri-operative high-dose-rate brachytherapy (PHDRBT) as accelerated minimal breast irradiation (AMBI) or anticipated boost (A-PHDRBT-boost).

Material And Methods: Patients older than 40, with clinical and radiological unifocal DCIS < 3 cm were considered potential candidates for accelerated partial breast irradiation (APBI) and were implanted during BCS using MITBI-technique. Patients who in final pathology reports showed free margins and no other microscopic tumor foci, received AMBI with PHDRBT (3.4 Gy BID in 5 days). Patients with adverse features received A-PHDRBT-boost with post-operative external beam radiotherapy (EBRT).

Results: Forty-one patients were implanted, and 36 were treated and analyzed. According to final pathology, 24 (67%) patients were suitable for AMBI and 12 (33%) were qualified for A-PHDRBT-boost. Reoperation rate for those with clear margins was 16.6% (6/36); this rate increased to 33% (4/12) for G3 histology, and 66% (4/6) were rescued using AMBI. Early complications were documented in 5 patients (14%). With a median follow-up of 97 (range, 42-138) months, 5-year rates of local, elsewhere, locoregional, and distant control were all 97.2%. 5-year ipsilateral breast tumor recurrence rates (IBTR) were 5.6% (2/36), 8.3% (2/24) for AMBI, and 0% (0/12) for A-PHDRBT-boost patients. Both instances of IBTR were confirmed G3 tumors in pre-operative biopsies; no IBTR was documented in G1-2 tumors. Cosmetic outcomes were excellent/good in 96% of AMBI vs. 67% in A-PHDRBT-boost ( = 0.034).

Conclusions: The MITBI-PHDRBT program allows selection of patients with excellent prognoses (G1-2 DCIS with negative margins and no multifocality), for whom AMBI could be a good alternative with low recurrence rate, decrease of unnecessary radiation, treatment logistics improvement, and over-treatment reduction. Patients whose pre-operative biopsy showed G3 tumor, presents with inferior local control and more risk of reoperation due to positive margins.
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http://dx.doi.org/10.5114/jcb.2020.101684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787199PMC
December 2020

Dose volume histogram constraints in patients with head and neck cancer treated with surgery and adjuvant HDR brachytherapy: A proposal of the head and neck and skin GEC ESTRO Working group.

Radiother Oncol 2021 01 15;154:128-134. Epub 2020 Sep 15.

Departments of Oncology, University of Navarra, Pamplona, Spain. Electronic address:

Background: The Head and Neck and Skin (HNS) Working group of the GEC-ESTRO acknowledges the lack of widely accepted Dose Volume Histogram (DVH) constraints in adjuvant head and neck brachytherapy and issues recommendations to minimize mandibular Osteoradionecrosis (ORN) and Soft Tissue Necrosis (STN).

Methods: A total of 227 patients with the diagnosis of head and neck cancer treated with surgery and adjuvant HDR brachytherapy alone or combined with other treatment modalities during the period 2000-2018 were analyzed.

Results: STN was observed in 28 out of 227 cases (12.3%) with an average time to appearance of 4.0 months. In previously unirradiated cases, there was a positive correlation between CTV size and STN (p = 0.017) and a trend towards significance between Total EQD2-DVH TV dose and STN (p = 0.06). The risk of STN in the absence of both factors (i.e, CTV < 15 cm and Total EQD2-DVH TV dose < 87 Gy) was 2%, with one factor present 15.7% and with both factors 66.7% (p = 0.001). ORN was observed in 13 out of 227 cases (5.7%) with an average time to appearance of 26.2 months. In unirradiated cases, ORN correlated with Total Physical Dose to Mandible (p = 0.027). Patients receiving Total Physical Doses greater than 61 Gy had a 20-fold increased risk of ORN.

Conclusions: In Unirradiated patients the panel recommends to avoid implantation of postoperative CTVs exceeding 15 cm at Total EQD2-DVH TV doses in excess of 87 Gy as well as to limit the irradiation of the Mandible to 61 Gy. In previously irradiated patients the panel cannot make a recommendation based on the available results.
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http://dx.doi.org/10.1016/j.radonc.2020.09.015DOI Listing
January 2021

Response to Escande et al.: Magnetic guided brachytherapy: Time for non-pelvic cancer? Example from tongue brachytherapy.

Radiother Oncol 2021 02 13;155:e3-e4. Epub 2020 Aug 13.

Unità Operativa Complessa di Radioterapia Oncologica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy.

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http://dx.doi.org/10.1016/j.radonc.2020.07.047DOI Listing
February 2021

Long-term results of Perioperative High Dose Rate Brachytherapy (PHDRB) and external beam radiation in adult patients with soft tissue sarcomas of the extremities and the superficial trunk: Final results of a prospective controlled study.

Radiother Oncol 2019 06 19;135:91-99. Epub 2019 Mar 19.

Department of Oncology, Clínica Universitaria de Navarra, University of Navarra, Pamplona, Spain. Electronic address:

Background: To analyze toxicity, patterns of failure, and survival in 106 adult patients with soft tissue sarcomas of the extremity and the superficial trunk treated in a prospective controlled trial of combined Perioperative High Dose Rate Brachytherapy (PHDRB) and external beam radiotherapy (EBRT).

Methods: Patients were treated with surgical resection and 16 Gy or 24 Gy of PHDRB for negative or close/positive margins, respectively. EBRT (45 Gy) was added postoperatively. Adjuvant chemotherapy was given to selected patients with high-grade tumors.

Results: The median follow-up was 7.1 years (range, 0.6-16.0). Grade ≥3 adverse events were observed in 22 patients (20.8%), and grade ≥4 events in 14 patients (13.2%). No grade 5 events were noted. Multivariate analysis (p = 0.003) found that Grade ≥3 toxic events increased with increasing implant volume (TV). Local control, locoregional control, and distant control rates at 5 and 10 years were 89% and 87%, 82% and 80% and 75% and 69%, respectively. Multivariate analysis (p = 0.024) found that positive margins correlated with decreased local control. Disease-free survival and overall survival rates at 5 and 10 years were 64% and 59% and 73% and 62%, respectively. In multivariate analysis, disease-free survival rates decreased with increasing tumor size (p = 0.0001) and inadequate margins (p = 0.024), and overall survival decreased with increasing tumor size (p = 0.001) and male gender (p = 0.039).

Conclusions: The combination of conservative surgery, high-dose PHDRB, and EBRT produces adequate function and local control in the majority of patients with soft tissue sarcomas of the extremities and the superficial trunk, including a substantial percentage of cases with positive margins. Patients with larger tumors are at a higher risk of complications, treatment failure, and cancer-related death and require an individualized treatment approach.
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http://dx.doi.org/10.1016/j.radonc.2019.02.011DOI Listing
June 2019

Personalized re-treatment strategy for uveal melanoma local recurrences after interventional radiotherapy (brachytherapy): single institution experience and systematic literature review.

J Contemp Brachytherapy 2019 Feb 28;11(1):54-60. Epub 2019 Feb 28.

Istituto di Oftalmologia, Università Cattolica del Sacro Cuore, Roma, Italy.

Purpose: To report the results of a patient's tailored therapeutic approach using a second course of interventional radiotherapy (brachytherapy) in patients with locally recurrent uveal melanoma.

Material And Methods: Patients who had already undergone ocular brachytherapy treated at our IOC (Interventional Oncology Center) were considered. Five patients who has received a second course of treatment with a plaque after local recurrences were included in our study. Re-irradiation was performed with Ruthenium-106 (prescribed dose to the apex 100 Gy) or with Iodine-125 plaques (prescribed dose to the apex 85 Gy). Moreover, a systematic literature search was conducted through three electronic databases, including Medline/PubMed, Scopus, and Embase.

Results: All patients were initially treated with Ruthenium-106 plaque; the re-irradiation was performed with Ruthenium-106 plaque in three cases and with Iodine in two cases. Mean time between the first and the second plaque was 56.8 months (range, 25-93 months). Local tumor control rate was 100%, no patient underwent secondary enucleation owing to re-treatment failure. Distant metastasis occurred in 1 patient after 6 months from re-treatment. After a median follow-up of 44.2 months (range, 26-65 months) from re-treatment, all patients experienced worsening of the visual acuity (median visual acuity was 0.42 at time of recurrence and decline to 0.24 at the most recent follow-up); cataract occurred in two cases, no patient developed scleral necrosis. We considered 2 papers for a systematic review.

Conclusions: In selected cases, especially in presence of marginal local recurrence, a personalized re-treatment strategy with a plaque may offer high probability of tumor control and organ preservation but worsening of visual acuity.
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http://dx.doi.org/10.5114/jcb.2019.82888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6431104PMC
February 2019

ENT COBRA ONTOLOGY: the covariates classification system proposed by the Head & Neck and Skin GEC-ESTRO Working Group for interdisciplinary standardized data collection in head and neck patient cohorts treated with interventional radiotherapy (brachytherapy).

J Contemp Brachytherapy 2018 Jun 30;10(3):260-266. Epub 2018 Jun 30.

Interdisciplinary Brachytherapy Unit, University of Lübeck - University Hospital S-H, Campus Lübeck, Germany.

Purpose: Clinical data collecting is expensive in terms of time and human resources. Data can be collected in different ways; therefore, performing multicentric research based on previously stored data is often difficult. The primary objective of the ENT COBRA (COnsortium for BRachytherapy data Analysis) ontology is to define a specific terminological system to standardized data collection for head and neck (H&N) cancer patients treated with interventional radiotherapy.

Material And Methods: ENT-COBRA is a consortium for standardized data collection for H&N patients treated with interventional radiotherapy. It is linked to H&N and Skin GEC-ESTRO Working Group and includes 11 centers from 6 countries. Its ontology was firstly defined by a multicentric working group, then evaluated by the consortium followed by a multi-professional technical commission involving a mathematician, an engineer, a physician with experience in data storage, a programmer, and a software expert.

Results: Two hundred and forty variables were defined on 13 input forms. There are 3 levels, each offering a specific type of analysis: 1. Registry level (epidemiology analysis); 2. Procedures level (standard oncology analysis); 3. Research level (radiomics analysis). The ontology was approved by the consortium and technical commission; an ad-hoc software architecture ("broker") remaps the data present in already existing storage systems of the various centers according to the shared terminology system. The first data sharing was successfully performed using COBRA software and the ENT COBRA Ontology, automatically collecting data directly from 3 different hospital databases (Lübeck, Navarra, and Rome) in November 2017.

Conclusions: The COBRA Ontology is a good response to the multi-dimensional criticalities of data collection, retrieval, and usability. It allows to create a software for large multicentric databases with implementation of specific remapping functions wherever necessary. This approach is well-received by all involved parties, primarily because it does not change a single center's storing technologies, procedures, and habits.
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http://dx.doi.org/10.5114/jcb.2018.76982DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6052377PMC
June 2018

Perioperative high-dose-rate brachytherapy in locally advanced and recurrent gynecological cancer: Final results of a Phase II trial.

Brachytherapy 2018 Sep - Oct;17(5):734-741. Epub 2018 May 24.

Department of Gynecology and Obstaetrics, Clínica Universitaria de Navarra, Pamplona, Navarre, Spain.

Purpose: To determine the long-term results of a Phase II trial of perioperative high-dose-rate brachytherapy (PHDRB) in primary advanced or recurrent gynecological cancer.

Methods And Materials: Fifty patients with locally advanced and recurrent gynecological cancer suitable for salvage surgery were included. Unirradiated patients (n = 25) received preoperative chemoradiation followed by surgery and PHDRB (16-24 Gy). Previously irradiated patients (n = 25) received surgery and PHDRB alone (32-40 Gy).

Results: Median followup was 11.5 years. Eight unirradiated patients (32%) developed Grade ≥3 toxic events including two fatal events. Local and locoregional control rates at 16 years were 87.3% and 78.9%, respectively. Sixteen-year disease-free and overall survival rates were 42.9% and 46.4%, respectively. Ten previously irradiated patients (40.0%) developed Grade ≥3 adverse events, including four fatal events. Local and locoregional control rates at 14 years were 59.6% and 42.6%, respectively. Fourteen-year disease-free and overall survival rates were 16.0% and 19.2%, respectively.

Conclusions: PHDRB allows effective salvage of a subset of unfavorable gynecological tumors with high-risk surgical margins. Toxicity was unacceptable at the initial dose levels but deescalation resulted in the absence of severe toxicity without a negative impact on locoregional control. A substantial percentage of patients remain alive and controlled at >10 years including a few previously irradiated cases with positive margins.
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http://dx.doi.org/10.1016/j.brachy.2018.04.007DOI Listing
March 2019

Radiation effects on antitumor immune responses: current perspectives and challenges.

Ther Adv Med Oncol 2018 18;10:1758834017742575. Epub 2018 Jan 18.

Programme in Solid Tumours and Biomarkers, Division of Oncology, Centre for Applied Biomedical Research (CIMA), IdiSNA, Navarra Institute for Health Research, Department of Histology and Pathology, University of Navarra, School of Medicine, Pamplona, Spain. Centro de Investigación Biomédica en Red de Cáncer (CIBERONC).

Radiotherapy (RT) is currently used in more than 50% of cancer patients during the course of their disease in the curative, adjuvant or palliative setting. RT achieves good local control of tumor growth, conferring DNA damage and impacting tumor vasculature and the immune system. Formerly regarded as a merely immunosuppressive treatment, pre- and clinical observations indicate that the therapeutic effect of RT is partially immune mediated. In some instances, RT synergizes with immunotherapy (IT), through different mechanisms promoting an effective antitumor immune response. Cell death induced by RT is thought to be immunogenic and results in modulation of lymphocyte effector function in the tumor microenvironment promoting local control. Moreover, a systemic immune response can be elicited or modulated to exert effects outside the irradiation field (so called abscopal effects). In this review, we discuss the body of evidence related to RT and its immunogenic potential for the future design of novel combination therapies.
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http://dx.doi.org/10.1177/1758834017742575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5784573PMC
January 2018

GEC-ESTRO ACROP recommendations for head & neck brachytherapy in squamous cell carcinomas: 1st update - Improvement by cross sectional imaging based treatment planning and stepping source technology.

Radiother Oncol 2017 02 23;122(2):248-254. Epub 2016 Nov 23.

Department of Radiotherapy (Radiooncology), Christian-Albrechts-University/UKSH-CK, Kiel, Germany.

The Head and Neck Working Group of the GEC-ESTRO (Groupe Européen de Curiethérapie - European Society for Therapeutic Radiology and Oncology) published in 2009 the consensus recommendations for low-dose rate, pulsed-dose rate and high-dose rate brachytherapy in head & neck cancers. The use of brachytherapy in combination with external beam radiotherapy and/or surgery was also covered as well as the use of brachytherapy in previously irradiated patients. Given the developments in the field, these recommendations needed to be updated to reflect up-to-date knowledge. The present update does not repeat basic knowledge which was published in the first recommendation but covers in a general part developments in (1) dose and fractionation, (2) aspects of treatment selection for brachytherapy alone versus combined BT+EBRT and (3) quality assurance issues. Detailed expert committee opinion intends to help the clinical practice in lip-, oral cavity-, oropharynx-, nasopharynx-, and superficial cancers. Different aspects of adjuvant treatment techniques and their results are discussed, as well the possibilities of salvage brachytherapy applications.
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http://dx.doi.org/10.1016/j.radonc.2016.10.008DOI Listing
February 2017

Perioperative high dose rate brachytherapy (PHDRB) in previously irradiated head and neck cancer: Results of a phase I/II reirradiation study.

Radiother Oncol 2017 02 13;122(2):255-259. Epub 2016 Oct 13.

Department of Oncology, Clínica Universidad de Navarra, Spain. Electronic address:

Background And Purpose: This study was undertaken to determine the feasibility of salvage surgery and PHDRB in patients with previously irradiated, recurrent head and neck cancer or second primary tumors arising in a previously irradiated field.

Methods And Materials: Sixty-three patients were treated with surgical resection and PHDRB. The PHDRB dose was 4Gy b.i.d.×8 (32Gy) for R0 resections and 4Gy b.i.d.×10 (40Gy) for R1 resections, respectively. Further external beam radiotherapy or chemotherapy was not given.

Results: Resections were categorized as R0 in 7 patients (11.1%) and R1 in 56 (88.9%). Thirty-four patients with R1 resections (54.0%) had microscopically positive margins, and 22 patients (34.9%) had close margins. Thirty-two patients (50.8%) developed RTOG grade 3 or greater adverse events including 3 fatal events. After a median follow-up of 6.8years, the 5-year locoregional control rate and 5-year overall survival rates were 55.0% and 35.6%, respectively.

Conclusions: Surgical resection and PHDRB is a successful treatment strategy in selected patients with previously irradiated head and neck cancer. Long-term locoregional control can be achieved in a substantial number of cases despite a high rate of inadequate surgical resections although at the expense of substantial toxicity.
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http://dx.doi.org/10.1016/j.radonc.2016.08.023DOI Listing
February 2017

ENT COBRA (Consortium for Brachytherapy Data Analysis): interdisciplinary standardized data collection system for head and neck patients treated with interventional radiotherapy (brachytherapy).

J Contemp Brachytherapy 2016 Aug 26;8(4):336-43. Epub 2016 Aug 26.

Department of Radiation Oncology - Gemelli-ART, Catholic University, Italy.

Purpose: Aim of the COBRA (Consortium for Brachytherapy Data Analysis) project is to create a multicenter group (consortium) and a web-based system for standardized data collection.

Material And Methods: GEC-ESTRO (Groupe Européen de Curiethérapie - European Society for Radiotherapy & Oncology) Head and Neck (H&N) Working Group participated in the project and in the implementation of the consortium agreement, the ontology (data-set) and the necessary COBRA software services as well as the peer reviewing of the general anatomic site-specific COBRA protocol. The ontology was defined by a multicenter task-group.

Results: Eleven centers from 6 countries signed an agreement and the consortium approved the ontology. We identified 3 tiers for the data set: Registry (epidemiology analysis), Procedures (prediction models and DSS), and Research (radiomics). The COBRA-Storage System (C-SS) is not time-consuming as, thanks to the use of "brokers", data can be extracted directly from the single center's storage systems through a connection with "structured query language database" (SQL-DB), Microsoft Access(®), FileMaker Pro(®), or Microsoft Excel(®). The system is also structured to perform automatic archiving directly from the treatment planning system or afterloading machine. The architecture is based on the concept of "on-purpose data projection". The C-SS architecture is privacy protecting because it will never make visible data that could identify an individual patient. This C-SS can also benefit from the so called "distributed learning" approaches, in which data never leave the collecting institution, while learning algorithms and proposed predictive models are commonly shared.

Conclusions: Setting up a consortium is a feasible and practicable tool in the creation of an international and multi-system data sharing system. COBRA C-SS seems to be well accepted by all involved parties, primarily because it does not influence the center's own data storing technologies, procedures, and habits. Furthermore, the method preserves the privacy of all patients.
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http://dx.doi.org/10.5114/jcb.2016.61958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5018530PMC
August 2016

Long-Term Results of a Phase II Trial of Concomitant Cisplatin-Paclitaxel Chemoradiation in Locally Advanced Cervical Cancer.

Int J Gynecol Cancer 2016 07;26(6):1162-8

Departments of *Oncology and †Gynecology and Obstetrics, Clínica Universidad de Navarra, University of Navarra, Pamplona, Navarre, Spain.

Objectives: The aim of this study was to determine the long-term results of a 7-week schedule of external beam radiation therapy, high dose rate brachytherapy, and weekly cisplatin and paclitaxel in patients with locally advanced carcinoma of the cervix.

Methods: Thirty-seven patients with International Federation of Gynecology and Obstetrics stages IB2 to IVa cervical cancer were treated with 40 mg/m per week of intravenous cisplatin and 50 mg/m per week of intravenous paclitaxel combined with 45 Gy of pelvic external beam radiation therapy and 28 to 30 Gy of high dose rate brachytherapy.

Results: Sixteen patients (43.2%) were able to complete the 6 scheduled cycles of chemotherapy. The median number of weekly chemotherapy cycles administered was 5. Thirty-six (16.2%) of 222 cycles of chemotherapy were not given because of toxicity. The mean dose intensity of cisplatin was 29.6 mg/m per week (95% confidence interval, 27.0-32.1); that of paclitaxel was 40.0 mg/m per week (95% confidence interval, 36.9-43.1). Thirty-four patients (91.8%) completed the planned radiation course in less than 7 weeks. Median radiation treatment length was 43 days. After a median follow-up of 6 years, 7 patients (18.9%) experienced severe (RTOG grade 3 or higher) late toxicity. No fatal events were observed. Ten patients have failed, 1 locally and 9 at distant sites. The 14-year locoregional control rate was 96.7%, and the 14-year freedom from systemic failure rate was 64.6%. Fourteen-year actuarial disease-free survival and overall survival rates were 44.8% and 50%, respectively.

Conclusions: This study demonstrates excellent very long-term results and tolerable toxicity although the target weekly dosage of cisplatin and paclitaxel needs to be adjusted in the majority of the patients.
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http://dx.doi.org/10.1097/IGC.0000000000000744DOI Listing
July 2016

Multicatheter breast implant during breast conservative surgery: Novel approach to deliver accelerated partial breast irradiation.

Brachytherapy 2016 Jul-Aug;15(4):485-494. Epub 2016 Apr 26.

Department of Oncology, University of Navarre, Pamplona, Spain.

Purpose: To assess the safety, feasibility, and efficacy of free-hand intraoperative multicatheter breast implant (FHIOMBI) and perioperative high-dose-rate brachytherapy (PHDRBT) in early breast cancer.

Methods And Materials: Patients with early breast cancer candidates for breast conservative surgery (BCS) were prospectively enrolled. Patients suitable for accelerated partial breast irradiation (APBI) (low or intermediate risk according GEC-ESTRO criteria) received PHDRBT (3.4 Gy BID × 10 in 5 days). Patients not suitable for APBI (high risk patients according GEC-ESTRO criteria) received PHDRBT boost (3.4 Gy BID × 4 in 2 days) followed by whole breast irradiation.

Results: From June 2007 to November 2014, 119 patients were treated and 122 FHIOMBI procedures were performed. Median duration of FHIOMBI was 25 minutes. A median of eight catheters (range, 4-14) were used. No severe intraoperative complications were observed. Severe early postoperative complications (bleeding) were documented in 2 patients (1.6%), wound healing complications in 3 (2.4%), and infection (mastitis or abscess) in 2 (1.6%). PHDRBT was delivered as APBI in 88 cases (72.1%) and as a boost in 34 (27.8%). The median clinical target volume T was 40.8 cc (range, 12.3-160.5); median D90 was 3.32 Gy (range, 3.11-3.85); median dose homogeneity index was 0.72 (range, 0.48-0.82). With a median followup of 38.4 months (range, 8.7-98.7) no local, elsewhere, or regional relapses were observed; there was only one distant failure in PHDRBT boost. No major (acute or late) RTOG grade 3 or higher were documented in any of the 119 patients treated with PHDRBT. Cosmetic outcome in APBI patients was excellent or good in (87.0%) and fair or poor in (11.9%) while in boost patients was excellent or good in (76.4%) and fair in (23.5%).

Conclusion: The FHIOMBI-PHDRBT program does not add complications to conservative surgery. It allows precise selection of APBI patients and offers excellent results in disease control and cosmetics. It also offers logistic advantages because it dramatically shortens the time of local treatment and avoids further invasive procedures.
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http://dx.doi.org/10.1016/j.brachy.2016.03.001DOI Listing
July 2017

Adjuvant radiation therapy in resected high-grade localized skeletal osteosarcomas treated with neoadjuvant chemotherapy: Long-term outcomes.

Radiother Oncol 2016 04 9;119(1):30-4. Epub 2016 Mar 9.

Department of Pediatrics, Clínica Universidad de Navarra, Pamplona, Spain.

Purpose: To assess long-term outcomes and toxicity of adjuvant radiotherapy in the post-surgical management of patients with resected high-grade skeletal osteosarcomas.

Methods And Materials: Seventy-two patients with primary resected osteosarcomas underwent adjuvant radiotherapy after neoadjuvant chemotherapy from December 1984 to December 2008. Local control (LC), overall survival (OS) and disease-free survival (DFS) were estimated using Kaplan-Meier methods. For survival outcomes potential associations were assessed in univariate and multivariate analyses using the Cox proportional hazards model.

Results: After a median follow-up of 174months (range, 33-363months), 10-year LC, DFS, and OS rates were 82%, 58%, and 73%, respectively. In the multivariate analysis only R1 margin status (p=0.02) remained significantly associated with LC. Patients with tumor necrosis <90% (p=0.04) and R1 resection margin (p=0.05) remained at a significantly higher risk of mortality on multivariate analysis. Six patients (8%) developed grade ⩾3 treatment-related chronic toxicity events. No grade 5 toxicities were reported.

Conclusions: A multimodal radiotherapy-containing approach is a well-tolerated component of treatment for patients with osteosarcomas undergoing programed resection, allowing low toxicity rates while maintaining high local control rates.
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http://dx.doi.org/10.1016/j.radonc.2016.02.029DOI Listing
April 2016

Dose escalation with external beam radiation therapy and high-dose-rate brachytherapy combined with long-term androgen deprivation therapy in high and very high risk prostate cancer: Comparison of two consecutive high-dose-rate schemes.

Brachytherapy 2016 Mar-Apr;15(2):127-35. Epub 2016 Jan 29.

Department of Radiation Oncology, Clínica Universitaria de Navarra, University of Navarra, Pamplona, Navarre, Spain. Electronic address:

Purpose: To compare rectal toxicity, urinary toxicity, and nadir+2 PSA relapse-free survival (bRFS) in two consecutive Phase II protocols of high-dose-rate (HDR) brachytherapy used at the authors institution from 2001 to 2012.

Methods And Materials: Patients with National Comprehensive Cancer Network high risk and very high risk prostate cancer enrolled in studies HDR4 (2001-2007, n = 183) and HDR2 (2007-2012, n = 56) were analyzed. Patients received minipelvis external beam radiation therapy/intensity-modulated external radiotherapy to 54 Gy and 2 years of androgen blockade along with HDR brachytherapy. HDR4 protocol consisted of four 4.75 Gy fractions delivered in 48 hours; the HDR2 protocol delivered two 9.5 Gy fractions in 24 hours. Average 2-Gy equivalent dose (α/β = 1.2) prostate D90 doses for the HDR4 and HDR2 groups were 89.8 Gy and 110.5 Gy, respectively (p = 0.0001). Both groups were well balanced regarding risk factors. Prior transurethral resection of the prostate was more frequent in the HDR2 group (p = 0.001).

Results: After a median followup of 7.4 years (range, 2-11.2), there was no difference in adverse grade ≥ 2 rectal events (HDR4 = 10.4% vs. HDR2 = 12.5%; p = ns) or grade ≥3 (HDR4 = 2.2% vs. HDR2 = 3.6%; p = ns). No differences in urinary grade ≥2 adverse events (HDR4 = 23% vs. HDR2 = 26.8%; p = ns) or grade ≥3 (HDR4 = 7.7% vs. HDR2 = 8.9%; p = ns) were detected. The 7-year bRFS for HDR4 and HDR2 protocols was 88.7% and 87.8%, respectively (p = ns).

Conclusions: HDR4 and HDR2 protocols produce similar results in terms of toxicity and bRFS at the intermediate time point of 7 years.
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http://dx.doi.org/10.1016/j.brachy.2015.12.008DOI Listing
November 2016

Three-Dimensional Power Doppler Ultrasound for Predicting Response and Local Recurrence After Concomitant Chemoradiation Therapy for Locally Advanced Carcinoma of the Cervix.

Int J Gynecol Cancer 2016 Mar;26(3):534-8

*Department of Obstetrics and Gynecology, School of Medicine, University of Navarra, Pamplona; †Department of Obstetrics and Gynecology, Hospital Garcia Orcoyen, Estella; and ‡Department of Radiation Oncology, School of Medicine, University of Navarra, Pamplona, Spain.

Objective: The aim of this study was to assess the potential role of 3-dimensional power Doppler ultrasound (3D-PDUS) for predicting clinical response and recurrence after chemoradiotherapy in advanced-stage cervical cancer.

Methods: This is a prospective study comprising a series of women with histological proven diagnosis of locally advanced stage (stage IB2-IVA) carcinoma of the cervix and submitted to chemoradiaton therapy. Before the start of chemoradiation therapy, all women were submitted to undergo transvaginal 3D-PDUS for assessing tumor volume and tumor vascularization. After finishing chemoradiation, all women were evaluated to assess clinical response. Complete clinical response was determined when no residual tumor was apparent. Partial clinical response (PCR) was determined when persistent residual tumor was observed and confirmed by histological analysis. Patients with PCR underwent salvage surgery. Local recurrence was defined as reappearance of the tumor within the pelvis at any time during follow-up.

Results: Thirty-nine women (mean age, 50.3 years; ranging from 30 to 81 years) were included in the study. Complete clinical response was achieved in 29 women (70.7%), whereas 10 women (24.4%) had PCR. Eight women (20.5%) had local recurrence during follow-up. We did not find statistical significant differences in tumor size, volume, and vascularization between those women who had complete clinical response and those who had PCR and between those who had local recurrence and those who had not.

Conclusions: A single 3D-PDUS assessment of tumor size and vascularization before treatment seems to be of limited value for predicting tumor response to chemoradiation therapy and for predicting tumor recurrence in women with locally advanced carcinoma of the cervix.
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http://dx.doi.org/10.1097/IGC.0000000000000641DOI Listing
March 2016

Salvage surgery and radiotherapy including intraoperative electron radiotherapy in isolated locally recurrent tumors: Predictors of outcome.

Radiother Oncol 2015 Aug 28;116(2):316-22. Epub 2015 Jul 28.

Department of Oncology, University of Navarre, Pamplona, Spain.

Purpose: To evaluate the influence of equivalent dose (EQD2) in clinical outcomes of patients with isolated locally recurrent tumors (ILRT), treated with salvage surgery and intra-operative electron beam radiation therapy (IOERT).

Methods And Materials: We retrospectively reviewed 128 patients with non-metastatic ILRT of different tissues (soft tissue sarcomas, head and neck, uterine, and colorectal). Patients had received salvage surgery (R0/R1/R2) and IOERT. Previously not irradiated patients had received additional external beam radiation therapy (EBRT).

Results: IOERT was delivered at a median dose of 15 Gy (range, 5-25 Gy). Seventy-five patients (60.9%) received additional EBRT of 46 Gy. Median EQD2 of salvage program was 62 Gy and median EQD2 of exclusive IORT was 31.2 Gy. Median follow-up was 19.2 months (range: 1.3-220). Thirty-one patients (24.2%) developed severe (grade 3-5) complications. New locoregional recurrence was documented in 86 (67.2%) of the 123 cases. Five-year rates were 31% for locoregional control, 57% for distant metastasis-free and 31% for overall survival. On multivariate analysis, R0-1 vs. R2 resection (HR 2.2, 95 CI: 1.2-4.1) was statistically significant for locoregional recurrence and EQD2 ⩾62 Gy for survival (HR 2.2, 95 CI: 1.1-4.1).

Conclusions: Surgical radicality (gross macroscopic resection) and radiation dose (EQD2 ⩾62 Gy in radiation salvage program) are the dominant prognostic factors beside ILRT histology. Modest rates of long-term disease control are expected when both factors are fulfilled.
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http://dx.doi.org/10.1016/j.radonc.2015.07.009DOI Listing
August 2015

Intraoperative Electron-Beam Radiation Therapy for Pediatric Ewing Sarcomas and Rhabdomyosarcomas: Long-Term Outcomes.

Int J Radiat Oncol Biol Phys 2015 Aug 2;92(5):1069-1076. Epub 2015 May 2.

Service of Radiation Oncology, Clínica Universidad de Navarra, Pamplona, Spain.

Purpose: To assess long-term outcomes and toxicity of intraoperative electron-beam radiation therapy (IOERT) in the management of pediatric patients with Ewing sarcomas (EWS) and rhabdomyosarcomas (RMS).

Methods And Materials: Seventy-one sarcoma (EWS n=37, 52%; RMS n=34, 48%) patients underwent IOERT for primary (n=46, 65%) or locally recurrent sarcomas (n=25, 35%) from May 1983 to November 2012. Local control (LC), overall survival (OS), and disease-free survival were estimated using Kaplan-Meier methods. For survival outcomes, potential associations were assessed in univariate and multivariate analyses using the Cox proportional hazards model.

Results: After a median follow-up of 72 months (range, 4-310 months), 10-year LC, disease-free survival, and OS was 74%, 57%, and 68%, respectively. In multivariate analysis after adjustment for other covariates, disease status (P=.04 and P=.05) and R1 margin status (P<.01 and P=.04) remained significantly associated with LC and OS. Nine patients (13%) reported severe chronic toxicity events (all grade 3).

Conclusions: A multimodal IOERT-containing approach is a well-tolerated component of treatment for pediatric EWS and RMS patients, allowing reduction or substitution of external beam radiation exposure while maintaining high local control rates.
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http://dx.doi.org/10.1016/j.ijrobp.2015.04.048DOI Listing
August 2015

Time to loading and locoregional control in perioperative high-dose-rate brachytherapy: The tumor bed effect revisited.

Brachytherapy 2015 Jul-Aug;14(4):565-70. Epub 2015 Apr 23.

Department of Gynecology, Clínica Universidad de Navarra, University of Navarre, Pamplona, Navarre, Spain; Instituto de Investigación Sanitaria de Navarra (IDISNA), Pamplona, Navarre, Spain.

Purpose: To determine whether the time to loading (TTL) affects locoregional control.

Methods And Materials: Locoregional control status was determined in 301 patients enrolled in several perioperative high-dose-rate brachytherapy (PHDRB) prospective studies conducted at the University of Navarre. The impact of the time elapsed from catheter implantation to the first PHDRB treatment (TTL) was analyzed. Patients treated with PHDRB alone (n = 113), mainly because of prior irradiation, received 32 Gy in eight twice-a-day treatments or 40 Gy in 10 twice-a-day treatments for negative or close/positive margins, respectively. Patients treated with PHDRB + external beam radiation therapy (EBRT) (n = 188) received 16 Gy in four twice-a-day treatments or 24 Gy in six twice-a-day treatments for negative or close/positive margins followed by 45 Gy of EBRT in 25 treatments.

Results: After a median followup of 6.5 years (range, 2-13.6+), 113 patients have failed (37.5%), 65 in the PHDRB-alone group (57.5%) and 48 in the combined PHDRB + EBRT group (25.5%). Patients who started PHDRB before Postoperative Day 5 had a 10-year locoregional control rate of 66.7% and patients who started PHDRB on Postoperative Day 5 or longer had a 10-year locoregional control rate of 51.8% (p = 0.009). Subgroup analysis detected that this difference was only observed in the recurrent cases treated with PHDRB alone (Subset 2; n = 99; p = 0.004). No correlation could be detected between locoregional control rate and TTL in the other patient subsets although a trend toward a decreased locoregional control rate after a longer TTL was observed when they were grouped together (p = 0.089).

Conclusions: Patients should start PHDRB as soon as possible to maximize locoregional control especially in those recurrent cases treated with PHDRB alone. The time effect in other disease scenarios is less clear.
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http://dx.doi.org/10.1016/j.brachy.2015.01.006DOI Listing
January 2016

Salvage wide resection with intraoperative electron beam therapy or HDR brachytherapy in the management of isolated local recurrences of soft tissue sarcomas of the extremities and the superficial trunk.

Brachytherapy 2015 Jan-Feb;14(1):62-70. Epub 2014 Oct 22.

Department of Oncology, University of Navarre, Pamplona, Spain.

Purpose: To assess the toxicity and efficacy of salvage wide resection (SWR) with intraoperative electron beam radiation therapy (IOERT) or perioperative high-dose-rate brachytherapy (PHDRB) in previously unirradiated patients (PUP) vs. previously irradiated patients (PIP) with isolated local recurrence of soft tissue sarcomas (STS) of the extremities and the superficial trunk.

Methods And Materials: PUP received SWR and IOERT/PHDRB with external beam radiation therapy. PIP received SWR and IOERT/PHDRB only.

Results: Fifty patients were analyzed retrospectively. PUP (n = 24; 48%) received IOERT (n = 13) or PHDRB (n = 11). PIP (n = 26; 52%) received IOERT (n = 10) or PHDRB (n = 16). Reintervention because of complications was not required in PUP. Nine of 26 (34%) PIP required reintervention (p = 0.01). After a median followup of 3.7 years (range, 0.2-18.3), the 5-year rates of locoregional control, distant control, and overall survival were 54%, 66%, and 56%, respectively. Five-year locoregional control was higher in PUP than in PIP (81% vs. 26%, p = 0.01) and in the extremity locations compared with trunk locations (68% vs. 28%, p = 0.001). Five-year overall survival was superior in unifocal vs. multifocal presentations (70% vs. 36%, p = 0.03) and for tumor sizes <4 vs. ≥4 cm (74% vs. 50%, p = 0.05).

Conclusions: Prior irradiation is the main determinant of locoregional control in patients with isolated local recurrence of STS. The locoregional control rates in PUP were similar to those described in primary STS. In PIP, SWR + IOERT/PHDRB reirradiation yielded modest locoregional control rates and was associated with significant morbidity, especially in PHDRB cases.
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http://dx.doi.org/10.1016/j.brachy.2014.09.003DOI Listing
June 2015

Anticipated intraoperative electron beam boost, external beam radiation therapy, and limb-sparing surgical resection for patients with pediatric soft-tissue sarcomas of the extremity: a multicentric pooled analysis of long-term outcomes.

Int J Radiat Oncol Biol Phys 2014 Sep;90(1):172-80

Service of Radiation Oncology, Clínica Universidad de Navarra, Pamplona, Spain.

Purpose: To perform a joint analysis of data from 3 contributing centers within the intraoperative electron-beam radiation therapy (IOERT)-Spanish program, to determine the potential of IOERT as an anticipated boost before external beam radiation therapy in the multidisciplinary treatment of pediatric extremity soft-tissue sarcomas.

Methods And Materials: From June 1993 to May 2013, 62 patients (aged <21 years) with a histologic diagnosis of primary extremity soft-tissue sarcoma with absence of distant metastases, undergoing limb-sparing grossly resected surgery, external beam radiation therapy (median dose 40 Gy) and IOERT (median dose 10 Gy) were considered eligible for this analysis.

Results: After a median follow-up of 66 months (range, 4-235 months), 10-year local control, disease-free survival, and overall survival was 85%, 76%, and 81%, respectively. In multivariate analysis after adjustment for other covariates, tumor size >5 cm (P=.04) and R1 margin status (P=.04) remained significantly associated with local relapse. In regard to overall survival only margin status (P=.04) retained association on multivariate analysis. Ten patients (16%) reported severe chronic toxicity events (all grade 3).

Conclusions: An anticipated IOERT boost allowed for external beam radiation therapy dose reduction, with high local control and acceptably low toxicity rates. The combined radiosurgical approach needs to be tested in a prospective trial to confirm these results.
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http://dx.doi.org/10.1016/j.ijrobp.2014.05.026DOI Listing
September 2014

Volume of high-dose regions and likelihood of locoregional control after perioperative high-dose-rate brachytherapy: do hotter implants work better?

Brachytherapy 2014 Nov-Dec;13(6):591-6. Epub 2014 Jun 11.

Department of Gynecology, Clínica Universidad de Navarra, Pamplona, Navarre, Spain.

Purpose: To determine whether perioperative high-dose-rate brachytherapy (PHDRB) implants with larger high-dose regions produce increased locoregional control.

Methods And Materials: Patients (n=166) enrolled in several PHDRB prospective studies conducted at the University of Navarre were analyzed. The PHDRB was given to total doses of 16Gy/4 b.i.d. or 24Gy/6 b.i.d. treatments for negative or close/positive margins along with 45Gy/25 Rx of external beam radiation therapy. The histogram-based generalized equivalent uniform dose (EUD) formulism was used to quantify and standardize the dose-volume histogram into 2-Gy equivalents. The region of interest analyzed included: tissue volume encompassed by the prescription isodose of 4Gy (TV100). Routine dose reporting parameters such as physical dose and single-point 2-Gy equivalent dose were used for reference.

Results: After a median followup of 7.4 years (range, 3-12+), 50 patients have failed, and 116 remain controlled at last followup. Overall, EUD was not different in the patients who failed compared with controls (89.1Gy vs. 86.5Gy; p=not significant). When patients were stratified by risk using the University of Navarre Predictive Model, very high-risk patients (i.e., tumors ≥3cm resected with close <1mm/positive margins) had an improved locoregional control with higher EUD values (p=0.028). This effect was not observed in low-, intermediate-, and high-risk University of Navarre Predictive Model categories.

Conclusions: In very high-risk patients, enlarged high-dose regions can produce a dose-response effect. Routine dose reporting methods such as physical dose and single-point 2-Gy equivalent dose may not show this effect, but it can be revealed by histogram-based EUD assessment.
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http://dx.doi.org/10.1016/j.brachy.2014.05.015DOI Listing
May 2015

Salvage brachytherapy in prostate local recurrence after radiation therapy: predicting factors for control and toxicity.

Radiat Oncol 2014 Apr 30;9:102. Epub 2014 Apr 30.

Department of Radiation Oncology, University Hospital of Sant Joan, Institute d'Investigació Sanitaria Pere Virgili (IISPV), Reus, Tarragona, Spain.

Purpose: To evaluate efficacy and toxicity after salvage brachytherapy (BT) in prostate local recurrence after radiation therapy.

Methods And Materials: Between 1993 and 2007, we retrospectively analyzed 56 consecutively patients (pts) undergoing salvage brachytherapy. After local biopsy-proven recurrence, pts received 145 Gy LDR-BT (37 pts, 66%) or HDR-BT (19 pts, 34%) in different dose levels according to biological equivalent doses (BED(2 Gy)). By the time of salvage BT, only 15 pts (27%) received ADT. Univariate and multivariate analyses were performed to identify predictors of biochemical control and toxicities. Acute and late genitourinary (GU) and gastrointestinal (GI) toxicities were graded using Common Terminology Criteria for Adverse Events (CTCv3.0).

Results: Median follow-up after salvage BT was 48 months. The 5-year FFbF was 77%. HDR and LDR late grade 3 GU toxicities were observed in 21% and 24%. Late grade 3 GI toxicities were observed in 2% (HDR) and 2.7% (LDR). On univariate analysis, pre-salvage prostate-specific antigen (PSA) > 10 ng/ml (p = 0.004), interval to relapse after initial treatment < 24 months (p = 0.004) and salvage HDR-BT doses BED(2 Gy) level < 227 Gy (p = 0.012) were significant in predicting biochemical failure. On Cox multivariate analysis, pre-salvage PSA, and time to relapse were significant in predicting biochemical failure. HDR-BT BED(2 Gy) (α/β 1.5 Gy) levels ≥ 227 (p = 0.013), and ADT (p = 0.049) were significant in predicting grade ≥ 2 urinary toxicity.

Conclusions: Prostate BT is an effective salvage modality in some selected prostate local recurrence patients after radiation therapy. Even, we provide some potential predictors of biochemical control and toxicity for prostate salvage BT, further investigation is recommended.
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http://dx.doi.org/10.1186/1748-717X-9-102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4019368PMC
April 2014

Limb-sparing management with surgical resection, external-beam and intraoperative electron-beam radiation therapy boost for patients with primary soft tissue sarcoma of the extremity: a multicentric pooled analysis of long-term outcomes.

Strahlenther Onkol 2014 Oct 9;190(10):891-8. Epub 2014 Apr 9.

Department of Oncology, Hospital General Universitario Gregorio Marañón, C/Doctor Esquerdo, 46-28007, Madrid, Spain.

Background Or Purpose: A joint analysis of data from three contributing centres within the intraoperative electron-beam radiation therapy (IOERT) Spanish program was performed to investigate the main contributions of IORT to the multidisciplinary treatment of high-risk extremity soft tissue sarcoma (STS).

Methods And Materials: Patients with an histologic diagnosis of primary extremity STS, with absence of distant metastases, undergoing limb-sparing surgery with radical intent, external beam radiotherapy (median dose 45 Gy) and IOERT (median dose 12.5 Gy) were considered eligible for participation in this study.

Results: From 1986-2012, a total of 159 patients were analysed in the study from three Spanish institutions. With a median follow-up time of 53 months (range 4-316 years), 5-year local control (LC) was 82 %. The 5-year IOERT in-field control, disease-free survival (DFS) and overall survival (OS) were 86, 62 and 72 %, respectively. On multivariate analysis, only microscopically involved margin (R1) resection status retained significance in relation to LC (HR 5.20, p < 0.001). With regard to IOERT in-field control, incomplete resection (HR 4.88, p = 0.001) and higher IOERT dose (≥ 12.5 Gy; HR 0.32, p = 0.02) retained a significant association in multivariate analysis.

Conclusion: From this joint analysis emerges the fact that an IOERT dose ≥ 12.5 Gy increases the rate of IOERT in-field control, but DFS remains modest, given the high risk of distant metastases. Intensified local treatment needs to be tested in the context of more efficient concurrent, neo- and adjuvant systemic therapy.
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http://dx.doi.org/10.1007/s00066-014-0640-2DOI Listing
October 2014

Phase II trial of image-based high-dose-rate interstitial brachytherapy for previously irradiated gynecologic cancer.

Brachytherapy 2014 May-Jun;13(3):219-24. Epub 2014 Feb 20.

Department of Gynaecology, University of Navarra, Pamplona, Navarre, Spain.

Purpose: To report the disease-free Grade ≥3 complication-free survival of a Phase II protocol of reirradiation with high-dose-rate (HDR) interstitial brachytherapy (ITB) in previously irradiated gynecologic cancer.

Methods And Materials: Fifteen patients with previously irradiated cervical (n = 6), endometrial (n = 6), and vulvovaginal tumors (n = 3) were treated with HDR-ITB alone to a median dose of 38 Gy in 8 b.i.d. fractions over 4 consecutive days. Prior treatments included surgery (n = 12; 80%), external irradiation (n = 15; 100%), and brachytherapy (n = 9; 60%). Average clinical target volume Size was 60.9 cc (range, 14.8-165.3 cc), and median time to reirradiation was 3.9 years (range, 0.4-22.7 years).

Results: With a median followup of 2.8 years (range, 1.2-9.2 years), 3 patients (20.0%) developed Grade ≥3 toxicity consisting of Grade 3 intestinal obstruction (n = 1), Grade 4 rectovesical fistula (n = 1), and Grade 5 intestinal obstruction (n = 1). Six patients remain alive and without evidence of disease at last followup. Two patients are alive with disease progression, and 7 patients have died, 4 of them from disease progression and 3 from other causes. The 2-year disease-free Grade ≥3 complication-free survival was 40%.

Conclusions: HDR-ITB alone is a reasonable salvage treatment option in a significant number of patients with previously irradiated gynecologic tumors.
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http://dx.doi.org/10.1016/j.brachy.2014.01.008DOI Listing
September 2014

Outcomes in a multi-institutional cohort of patients treated with intraoperative radiation therapy for advanced or recurrent renal cell carcinoma.

Int J Radiat Oncol Biol Phys 2014 Mar 8;88(3):618-23. Epub 2014 Jan 8.

Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts. Electronic address:

Purpose/objective(s): This study aimed to analyze outcomes in a multi-institutional cohort of patients with advanced or recurrent renal cell carcinoma (RCC) who were treated with intraoperative radiation therapy (IORT).

Methods And Materials: Between 1985 and 2010, 98 patients received IORT for advanced or locally recurrent RCC at 9 institutions. The median follow-up time for surviving patients was 3.5 years. Overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS) were estimated with the Kaplan-Meier method. Chained imputation accounted for missing data, and multivariate Cox hazards regression tested significance.

Results: IORT was delivered during nephrectomy for advanced disease (28%) or during resection of locally recurrent RCC in the renal fossa (72%). Sixty-nine percent of the patients were male, and the median age was 58 years. At the time of primary resection, the T stages were as follows: 17% T1, 12% T2, 55% T3, and 16% T4. Eighty-seven percent of the patients had a visibly complete resection of tumor. Preoperative or postoperative external beam radiation therapy was administered to 27% and 35% of patients, respectively. The 5-year OS was 37% for advanced disease and 55% for locally recurrent disease. The respective 5-year DSS was 41% and 60%. The respective 5-year DFS was 39% and 52%. Initial nodal involvement (hazard ratio [HR] 2.9-3.6, P<.01), presence of sarcomatoid features (HR 3.7-6.9, P<.05), and higher IORT dose (HR 1.3, P<.001) were statistically significantly associated with decreased survival. Adjuvant systemic therapy was associated with decreased DSS (HR 2.4, P=.03). For locally recurrent tumors, positive margin status (HR 2.6, P=.01) was associated with decreased OS.

Conclusions: We report the largest known cohort of patients with RCC managed by IORT and have identified several factors associated with survival. The outcomes for patients receiving IORT in the setting of local recurrence compare favorably to similar cohorts treated by local resection alone suggesting the potential for improved DFS with IORT.
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http://dx.doi.org/10.1016/j.ijrobp.2013.11.207DOI Listing
March 2014

Prognostic value of external beam radiation therapy in patients treated with surgical resection and intraoperative electron beam radiation therapy for locally recurrent soft tissue sarcoma: a multicentric long-term outcome analysis.

Int J Radiat Oncol Biol Phys 2014 Jan;88(1):143-50

Service of Radiation Oncology, Clínica Universitaria, Universidad de Navarra, Pamplona, Spain.

Background: A joint analysis of data from centers involved in the Spanish Cooperative Initiative for Intraoperative Electron Radiotherapy was performed to investigate long-term outcomes of locally recurrent soft tissue sarcoma (LR-STS) patients treated with a multidisciplinary approach.

Methods And Materials: Patients with a histologic diagnosis of LR-STS (extremity, 43%; trunk wall, 24%; retroperitoneum, 33%) and no distant metastases who underwent radical surgery and intraoperative electron radiation therapy (IOERT; median dose, 12.5 Gy) were considered eligible for participation in this study. In addition, 62% received external beam radiation therapy (EBRT; median dose, 50 Gy).

Results: From 1986 to 2012, a total of 103 patients from 3 Spanish expert IOERT institutions were analyzed. With a median follow-up of 57 months (range, 2-311 months), 5-year local control (LC) was 60%. The 5-year IORT in-field control, disease-free survival (DFS), and overall survival were 73%, 43%, and 52%, respectively. In the multivariate analysis, no EBRT to treat the LR-STS (P=.02) and microscopically involved margin resection status (P=.04) retained significance in relation to LC. With regard to IORT in-field control, only not delivering EBRT to the LR-STS retained significance in the multivariate analysis (P=.03).

Conclusion: This joint analysis revealed that surgical margin and EBRT affect LC but that, given the high risk of distant metastases, DFS remains modest. Intensified local treatment needs to be further tested in the context of more efficient concurrent, neoadjuvant, and adjuvant systemic therapy.
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http://dx.doi.org/10.1016/j.ijrobp.2013.10.021DOI Listing
January 2014
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