Moreno-Jimenez, M. (Marta)
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- Hypofractionated radiation therapy and temozolomide in patients with glioblastoma and poor prognostic factors. A prospective, single-institution experience(Public Library of Science (PLoS), 2019) Arbizu, J. (Javier); Garcia-de-Eulate, R. (Reyes); Aristu-Mendioroz, J.J. (José Javier); Domínguez-Echávarri, P.D. (Pablo Daniel); Arbea-Moreno, L. (Leire); Tejada-Solis, S. (Sonia); Jablonska, P.A. (Paola Anna); Diez-Valle, R. (Ricardo); Idoate, M.A. (Miguel Ángel); Ramos, L. (Luis); Gallego-Perez-Larraya, J. (Jaime); Moreno-Jimenez, M. (Marta)Background: Hypofractionated radiation therapy is a feasible and safe treatment option in elderly and frail patients with glioblastoma. The aim of this study was to evaluate the effectiveness of hypofractionated radiation therapy with concurrent temozolomide in terms of feasibility and disease control in primary glioblastoma patients with poor prognostic factors other than advanced age, such as post-surgical neurological complications, high tumor burden, unresectable or multifocal lesions, and potential low treatment compliance due to social factors or rapidly progressive disease. Material and methods: GTV included the surgical cavity plus disease visible in T1WI-MRI, FLAIR-MRI and in the MET-uptake. The CTV was defined as the GTV plus 1.5-2 cm margin; the PTV was the CTV+0.3 cm margin. Forty, fourty-five, and fifty grays in 15 fractions were prescribed to 95% of PTV, CTV, and GTV, respectively. Treatment was delivered using IMRT or the VMAT technique. Simultaneously, 75 mg/m2/day of temozolomide were administered. Results: Between January 2010 and November 2017, we treated a total of 17 patients. The median age at diagnosis was 68-years; median KPS was 50-70%. MGMT-methylation status was negative in 5 patients, and 8 patients were IDH-wildtype. Eight of 18 patients were younger than 65-years. Median tumor volume was 26.95cc; median PTV volume was 322cc. Four lesions were unresectable; 6 patients underwent complete surgical resection. Median residual volume was 1.14cc. Progression-free survival was 60% at 6 months, 33% at 1-year and 13% at 2-years (median OS = 7 months). No acute grade 3-5 toxicities were documented. Symptomatic grade 3 radiation necrosis was observed in one patient. Conclusions: Patients with poor clinical factors other than advanced age can be selected for hypofractionated radiotherapy. The OS and PFS rates obtained in our series are similar to those in patients treated with standard fractionation, assuring good treatment adherence, low rates of toxicity and probable improved cost-effectiveness.
- Radioterapia combinada con quimioterapia en el tratamiento del cáncer de pulmón(Ediciones Universidad de Navarra, 2007) Aristu-Mendioroz, J.J. (José Javier); Moreno-Jimenez, M. (Marta)El empleo conjunto de radioterapia y quimioterapia en el cáncer de pulmón no metastásico (microcítico y no microcítico) permite combi- nar los benefi cios de la radioterapia en términos de control local con aquellos conseguidos por la quimioterapia erradicando la enfermedad micrometastásica. Diversos estudios aleatorizados han demostrado que la radioterapia radical combinada con quimioterapia mejora la supervi- vencia de estos pacientes, a expensas de un incremento de la toxicidad. El desarrollo tecnológico y los avances en programas informáticos han posibilitado la introducción de nuevos aceleradores lineales comunicados con sofi sticados sistemas de planifi cación tridimensional que permiten administrar dosis mayores de irradiación al volumen tumoral diana y menores dosis de irradiación sobre estructuras sanas (pulmón, corazón, esófago y médula espinal). El resultado fi nal es un incremento del índice terapéutico debido a un probable benefi cio en el control local y una disminución de los efectos adversos de la irradiación. El volumen de irradiación, la dosis total a administrar, el fraccionamiento de la dosis, el tipo de esquema de combinación de la radioterapia con la quimiotera- pia, así como la infl uencia en la supervivencia de la irradiación cerebral profi láctica en el caso del cáncer microcítico de pulmón son temas de discusión en la actualidad. INGLÉS: The combination of radiotherapy and chemotherapy in lung cancer (locally advanced non-small and small cell) may offer the benefits of radiotherapy in terms of local control and those of chemotherapy in terms of reducing metastatic dissemination of the disease. Several randomized studies have showed that radical radiotherapy combined with chemotherapy improves the survival of these patients at the expense of an increase in toxicity. The technological development and the improvements in software have allowed the introduction of new linear accelerators and a three-dimensional planning system with the intention of delivering higher irradiation doses in the tumor target, and minimizing the dose in adjacent normal tissues (lung, heart, esophagus and spinal cord). The volume of irradiation, the total dose, the fractionation, the schedule for the combination of radiotherapy and chemotherapy, as well as the influence of the prophylactic cranial irradiation in small cell lung cancer are points for discussion at the moment.
- Radioterapia estereotáctica(Gobierno de Navarra, 2009) Ciérvide, R. (R.); Guridi-Legarra, J. (Jorge); Aristu-Mendioroz, J.J. (José Javier); Arbea-Moreno, L. (Leire); Ramos, L.I. (Luis Isaac); Zubieta, J.L. (José L.); Azcona-Armendariz, J.D. (Juan Diego); Moreno-Jimenez, M. (Marta)La radioterapia con técnica estereotáctica es una modalidad de radioterapia externa que utiliza un sistema de coordenadas tridimensionales independientes del paciente para la localización precisa de la lesión. También se caracteriza porque los haces de irradiación son altamente conformados, precisos y convergentes sobre la lesión que hacen posible la administración de dosis muy altas de radioterapia sin incrementar la irradiación de los órganos o estructuras sanas adyacentes. Cuando el procedimiento se realiza en una sesión de tratamiento se denomina radiocirugía y si se administra en varias sesiones se denomina radioterapia estereotáctica. Se precisa de sistemas de fijación e inmovilización del paciente especiales (guías o marcos estereotácticos) y dispositivos de radioterapia capaces de generar haces muy conformados (acelerador lineal, gammaknife, cyberknife, tomoterapia, ciclotrones). La radioterapia estereotáctica moderna utiliza marcas radioopacas intratumorales o sistemas de imágenes de TAC incluidos en el dispositivo de irradiación, que permiten una precisa localización de las lesiones móviles en cada sesión de tratamiento. Además, los avances tecnológicos hacen posible coordinar los movimientos de la lesión en la respiración con la unidad de radioterapia (gaiting y tracking) de forma que pueden estrecharse al máximo los márgenes y por lo tanto excluir un mayor volumen de tejido sano La radiocirugía está indicada principalmente en lesiones cerebrales benignas o malignas menores de 3-4 centímetros (malformaciones arteriovenosas, neurinomas, meningiomas, metástasis cerebrales) y la radioterapia estereotáctica se administra fundamentalmente en tumores de localización extracraneal que requieran una alta conformación y precisión como cáncer precoz de pulmón inoperable y metástasis hepáticas.
- Tratamiento radioterápico del cáncer mama: estándares y nuevas tendencias. Irradiación parcial acelerada de la mama(Ediciones Universidad de Navarra, 2008) Gomez-Iturriaga, A. (Alfonso); Martinez-Monge, R. (Rafael); Moreno-Jimenez, M. (Marta)Radiotherapy as a part of the breast cancer treatment has evolved in the last decades. Post-mastectomy radiotherapy produces a substantial reduction in the risk of local recurrence as well as a moderate, but definitive reduction in long-term breast cancer mortality in women at high risk of locoregional failure. Whole-breast irradiation, as part of breast-conservation therapy, has well-established results with good cosmesis, and low toxicity. Results from the BCT trials suggest that the risk for ipsilateral breast cancer recurrence resides within close proximity to the original tumor site. This has led investigators to consider the role of an accelerated and more tumor bed-focused course of radiotherapy. Accelerated partial-breast irradiation (APBI) is a collection of radiotherapy techniques that deliver higher daily doses of radiation to the surgical cavity with margin over a shorter time than whole breast irradiation (from 6-6.5 weeks to 1 week). Early results of this approach have demonstrated excellent local control, minimal acute toxicity, and are more convenient for the patient. Phase III randomized clinical trials are currently underway to assess local control, acute and chronic toxicities. APBI extend the choise of breast conservation
- A method using 4D dose accumulation to quantify the interplay effect in lung stereotactic body radiation therapy(IOP Publishing, 2021) Burguete, J. (Javier); Azcona-Armendariz, J.D. (Juan Diego); Moreno-Jimenez, M. (Marta); Huesa-Berral, C. (Carlos)The purpose of this study was to devise and evaluate a method to quantify the dosimetric uncertainty produced by the interplay between the movement of multileaf collimator and respiratory motion in lung stereotactic body radiation therapy. The method calculates the dose distribution for all control points from a dynamic treatment in all respiratory phases. The methodology includes some characteristics of a patient's irregular breathing patterns. It selects, for each control point, the phases with maximum and minimum mean dose over the tumor and their corresponding adjacent phases, whenever necessary. According to this selection, the dose matrices from each control point are summed up to obtain two dose distributions in each phase, which are accumulated in the reference phase subsequently by deformable image registration (DIR). D 95 and [Formula: see text] were calculated over those accumulated dose distributions for Gross Tumor Volume (GTV), Planning Target Volume-based on Internal Target Volume approach-and Evaluation Target Volume (ETV), a novel concept that applies to 4D dose accumulation. With the ETV, DIR and interplay uncertainties are separated. The methodology also evaluated how variations in the breathing rate and field size affects the mean dose received by the GTV. The method was applied retrospectively in five patients treated with intensity modulated radiotherapy-minimum area defined by the leaves configuration at any control point was at least 4 cm2. Uncertainties in tumor coverage were small (in most patients, changes on D 95 and [Formula: see text] were below 2% for GTV and ETV) but significant over- and under-dosages near ETV, which can be accentuated by highly irregular breathing. Uncertainties in mean dose for GTV tended to decrease exponentially with increasing field size and were reduced by an increase of breathing rate. The implementation of this method would be helpful to assess treatment quality in patients with irregular breathing. Furthermore, it could be used to study interplay uncertainties when small field sizes are used.
- A novel concept to include uncertainties in the evaluation of stereotactic body radiation therapy after 4D dose accumulation using deformable image registration(Wiley, 2019) Aristu-Mendioroz, J.J. (José Javier); Barbes-Fernandez, B. (Benigno); Burguete, J. (Javier); Azcona-Armendariz, J.D. (Juan Diego); Moreno-Jimenez, M. (Marta); Huesa-Berral, C. (Carlos)Purpose: To use four-dimensional (4D) dose accumulation based on deformable image registration (DIR) to assess dosimetric uncertainty in lung stereotactic body radiation therapy (SBRT) treatment planning. A novel concept, the Evaluation Target Volume (ETV), was introduced to achieve this goal. Methods: The internal target volume (ITV) approach was used for treatment planning for 11 patients receiving lung SBRT. Retrospectively, 4D dose calculation was done in Pinnacle v9.10. Total dose was accumulated in the reference phase using DIR with MIM. DIR was validated using landmarks introduced by an expert radiation oncologist. The 4D and three-dimensional (3D) dose distributions were compared within the gross tumor volume (GTV) and the planning target volume (PTV) using the D95 and Dmin (calculated as Dmin,0.035cc ) metrics. For lung involvement, the mean dose and V20 , V10 , and V5 were used in the 3D to 4D dose comparison, and Dmax (D0.1cc ) was used for all other organs at risk (OAR). The new evaluation target volume (ETV) was calculated by expanding the GTV in the reference phase in order to include geometrical uncertainties of the DIR, interobserver variability in the definition of the tumor, and uncertainties of imaging and delivery systems. D95 and Dmin,0.035cc metrics were then calculated on the basis of the ETV for 4D accumulated dose distributions, and these metrics were compared with those calculated from the PTV for 3D planned dose distributions. Results: The target registration error (TRE) per spatial component was below 0.5 ± 2.1mm for all our patients. For five patients, dose degradation above 2% (>4% in 2 patients) was found in the PTV after 4D accumulation and attributed to anatomical variations due to breathing. Comparison of D95 and Dmin,0.035cc metrics showed that the ETV (4D accumulated dose) estimated substantially lower coverage than the PTV (3D planning dose): in six out of the 11 cases, and for at least for one of the two metrics, coverage estimated by ETV was at least 5% lower than that estimated by PTV. Furthermore, the ETV approach revealed hot and cold spots within its boundaries. Conclusions: A workflow for 4D dose accumulation based on DIR has been devised. Dose degradation was attributed to respiratory motion. To overcome limitations in the PTV for the purposes of evaluating DIR-based 4D accumulated dose distributions, a new concept, the ETV, was proposed. This concept appears to facilitate more reliable dose evaluation and a better understanding of dosimetric uncertainties due to motion and deformation.
- A novel concept to include uncertainties in the evaluation of stereotactic body radiation therapy after 4D dose accumulation using deformable image registration(Wiley, 2019) Burguete-Mas, F.J. (Francisco Javier); Aristu-Mendioroz, J.J. (José Javier); Barbes-Fernandez, B. (Benigno); Azcona-Armendariz, J.D. (Juan Diego); Moreno-Jimenez, M. (Marta); Huesa-Berral, C. (Carlos)Purpose: To use four-dimensional (4D) dose accumulation based on deformable image registration (DIR) to assess dosimetric uncertainty in lung stereotactic body radiation therapy (SBRT) treatment planning. A novel concept, the Evaluation Target Volume (ETV), was introduced to achieve this goal. Methods: The internal target volume (ITV) approach was used for treatment planning for 11 patients receiving lung SBRT. Retrospectively, 4D dose calculation was done in Pinnacle v9.10. Total dose was accumulated in the reference phase using DIR with MIM. DIR was validated using landmarks introduced by an expert radiation oncologist. The 4D and three-dimensional (3D) dose distributions were compared within the gross tumor volume (GTV) and the planning target volume (PTV) using the D95 and Dmin (calculated as Dmin,0.035cc ) metrics. For lung involvement, the mean dose and V20 , V10 , and V5 were used in the 3D to 4D dose comparison, and Dmax (D0.1cc ) was used for all other organs at risk (OAR). The new evaluation target volume (ETV) was calculated by expanding the GTV in the reference phase in order to include geometrical uncertainties of the DIR, interobserver variability in the definition of the tumor, and uncertainties of imaging and delivery systems. D95 and Dmin,0.035cc metrics were then calculated on the basis of the ETV for 4D accumulated dose distributions, and these metrics were compared with those calculated from the PTV for 3D planned dose distributions. Results: The target registration error (TRE) per spatial component was below 0.5 ± 2.1mm for all our patients. For five patients, dose degradation above 2% (>4% in 2 patients) was found in the PTV after 4D accumulation and attributed to anatomical variations due to breathing. Comparison of D95 and Dmin,0.035cc metrics showed that the ETV (4D accumulated dose) estimated substantially lower coverage than the PTV (3D planning dose): in six out of the 11 cases, and for at least for one of the two metrics, coverage estimated by ETV was at least 5% lower than that estimated by PTV. Furthermore, the ETV approach revealed hot and cold spots within its boundaries. Conclusions: A workflow for 4D dose accumulation based on DIR has been devised. Dose degradation was attributed to respiratory motion. To overcome limitations in the PTV for the purposes of evaluating DIR-based 4D accumulated dose distributions, a new concept, the ETV, was proposed. This concept appears to facilitate more reliable dose evaluation and a better understanding of dosimetric uncertainties due to motion and deformation.
- Repeated stereotactic radiosurgery for recurrent brain metastases: An effective strategy to control intracranial oligometastatic disease(Elsevier, 2020) Gil-Bazo, I. (Ignacio); Aristu-Mendioroz, J.J. (José Javier); Domínguez-Echávarri, P.D. (Pablo Daniel); Martín-Pastor, S.M. (Santiago Mariano); Arbea-Moreno, L. (Leire); Ramos, L.I. (Luis Isaac); Martín-Pastor, M. (Manuel); Jablonskaa, P.A. (Paola Anna); Serrano-Tejero, D. (Diego); Gimeno-Morales, M. (Marta); Calvo-González, A. (Alfonso); Moreno-Jimenez, M. (Marta)Due to improvements in systemic therapies and longer survivals, cancer patients frequently present with re- current brain metastases (BM). The optimal therapeutic strategies for limited brain relapse remain undefined. We analyzed tumor control and survival in patients treated with salvage focal radiotherapy in our center. Thirty- three patients with 112 BM received salvage stereotactic radiosurgery (SRS) or fractionated stereotactic radio- therapy (FSRT) for local or regional recurrences. Local progression was observed in 11 BM (9.8 %). After 1 year, 72 % of patients were free of distant brain failure, and the 2-year overall survival (OS) was 37.7 %. No increase in toxicity or neurologically related deaths were observed. The 2- and 3-year whole brain radiation therapy free survival (WFS) rates were 92.9 % and 77.4 %, respectively. Hence, focal radiotherapy is a feasible salvage of recurrent BM in selected group of patients with limited brain disease, achieving a maintained intracranial control and less neurological toxicity.
- A population pharmacodynamic model for lactate dehydrogenase and neuron specific enolase to predict tumor progression in small cell lung cancer patients(Springer Link, 2014) Martin-Algarra, S. (Salvador); Ribba, B. (B.); Troconiz, I.F. (Iñaki F.); Lopez-Picazo, J.M. (José M.); Buil-Bruña, N (Núria); Moreno-Jimenez, M. (Marta)The development of individualized therapies poses a major challenge in oncology. Significant hurdles to overcome include better disease monitoring and early prediction of clinical outcome. Current clinical practice consists of using Response Evaluation Criteria in Solid Tumors (RECIST) to categorize response to treatment. However, the utility of RECIST is restricted due to limitations on the frequency of measurement and its categorical rather than continuous nature. We propose a population modeling framework that relates circulating biomarkers in plasma, easily obtained from patients, to tumor progression levels assessed by imaging scans (i.e., RECIST categories). We successfully applied this framework to data regarding lactate dehydrogenase (LDH) and neuron specific enolase (NSE) concentrations in patients diagnosed with small cell lung cancer (SCLC). LDH and NSE have been proposed as independent prognostic factors for SCLC. However, their prognostic and predictive value has not been demonstrated in the context of standard clinical practice. Our model incorporates an underlying latent variable (“disease level”) representing (unobserved) tumor size dynamics, which is assumed to drive biomarker production and to be influenced by exposure to treatment; these assumptions are in agreement with the known physiology of SCLC and these biomarkers. Our model predictions of unobserved disease level are strongly correlated with disease progression measured by RECIST criteria. In conclusion, the proposed framework enables prediction of treatment outcome based on circulating biomarkers and therefore can be a powerful tool to help clinicians monitor disease in SCLC.
- 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(Elsevier, 2019) Gimeno-Morales, M. (Marta); San-Julian, M. (Mikel); Cambeiro, M. (Mauricio); NO USAR Arbea, L. (Leire); Jablonska, P.A. (Paola Anna); Moreno-Jimenez, M. (Marta); Amillo, S. (Santiago); Aristu, J. (Javier); Lecanda, F. (Fernando); Martinez-Monge, R. (Rafael)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 (TV100). 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.