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Background: Primary central nervous system germ cell tumors (GCT) are rare neoplasms in pediatrics. Treatment depends on the histological subtype and extent of the disease. Overall survival (OS) is above 90% for germinomas and 70%-80% for nongerminomatous GCT (NGGCT) in high-income countries (HIC) while data are usually lacking for patients in Low-Middle Income country (LMIC). Objective: This study aims to describe the experience of treating patients with CNS GCT in four of eight countries, members of the Asociación de Hemato-Oncología Pediátrica de Centro América (AHOPCA), and determine their 5-year OS. Design/methods: We conducted a retrospective chart review of patients treated for CNS GCT. Epidemiological and clinical characteristics, histology, treatment modalities, and outcomes were analyzed. Results: From 2001 to 2021, 48 patients were included: 22 from Guatemala, 18 from Nicaragua, three from the Dominican Republic, and five from El Salvador. Thirty-one (64.6%) were boys; the median age at diagnosis was 10.2 years (range: 1 to 17 years). Presenting symptoms were headaches (n = 24, 50%), visual disturbances (n = 17, 35.4%), vomiting (n = 12, 25%), nausea (n = 8, 16.7%), and diabetes insipidus (n = 7, 14.6%). Two patients with NGGCT presented with precocious puberty. Biopsy or tumor resection was performed in 38 cases (79.2%): 23 (88.4%) germinomas, 11 (78.6%) NGGCT, and four (50%) CNS GCT. Eight patients were diagnosed and treated based on CSF tumor marker elevation; four germinomas (BHCG 11.32-29.41 mUI/mL) and four NGGCT (BHCG 84.43-201.97 mUI/mL or positive AFP > 10 UI/mL). Tumor locations included suprasellar (n = 17, 35.4%), pineal (n = 13, 27.1%), thalamus/basal ganglia (n = 5, 10.4%), other (n = 12, 25%), and one bifocal. Four (8.3%) had metastatic disease, and six had positive CSF; staging data were incomplete in 25 patients (52%). Patients were treated with varied chemotherapy and radiotherapy modalities. Nine patients had incomplete data regarding treatment. Five-year OS was 65% (68% for germinoma, 50.6% for NGGCT, and 85.7% for unclassified GCT). Conclusions: Germinoma was the most common histology, and there was a male predominance. More than half of patients had incomplete staging data and treatment was variable across the region. OS is lower compared to HIC. Standardized treatment protocols will aid in adequate staging and treatment planning, prevent complications, and improve survival.
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Introduction: Data on medulloblastoma outcomes and experiences in low- and middle-income countries, especially in Latin America, is limited. This study examines challenges in Mexico's healthcare system, focusing on assessing outcomes for children with medulloblastoma in a tertiary care setting. Methods: A retrospective analysis was conducted, involving 284 patients treated at 21 pediatric oncology centers in Mexico. Results: High-risk patients exhibited markedly lower event-free survival than standard-risk patients (43.5% vs. 78.3%, p<0.001). Influential factors on survival included anaplastic subtype (HR 2.4, p=0.003), metastatic disease (HR 1.9, p=0.001); residual tumor >1.5cm², and lower radiotherapy doses significantly impacted event-free survival (EFS) and overall survival (OS). Platinum-based chemotherapy showed better results compared to the ICE protocol in terms of OS and EFS, which was associated with higher toxicity. Patients under 3 years old displayed notably lower OS and EFS compared to older children (36.1% vs. 55.9%, p=0.01).
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Background Although international publications on radiosurgery have increased exponentially, reports of heterogeneous series treated with linear accelerator (LINAC) are scarce. Since most intracranial tumors are irregular in size and not spherical, LINACs (Elekta Precise®, Elekta AB, Sweden), fitted with a multi-leaf collimator, allow for precise stereotactic radiosurgery for the entire tumor. Aim To evaluate the effects of LINAC on an outpatient basis with patients diagnosed with various intracranial malignancies. Methodology A retrospective observational study of a series of cases of patients with intracranial lesions treated at the Institute of Oncology and Radiobiology using LINAC was carried out from October 2019 to May 2021 to evaluate the therapeutic results of radiosurgery in patients with intracranial tumors. Results A total of 22 lesions in 20 patients were treated with LINAC. The average age of the patients was 49.7, and the male-female ratio was 1:2. The cases consisted were mostly vestibular schwannoma (7 lesions), metastases from breast cancer (3 lesions), and tuberculum sellae meningioma (2 lesions). The prescription dose covered 99% of the planning target volume in 16 lesions (72.7%) and 100% in six lesions (27.3%) (prescription volume). In meningiomas and schwannomas, doses between 12 and 14 Gy were used, in plasmacytoma 13 Gy, in pilocytic astrocytoma 14 Gy, in cavernoma 15 Gy, in breast cancer metastasis between 18 and 20 Gy, and in lung cancer metastasis 22 Gy. When evaluating local control, 11 patients exhibited stable findings at the six-month control while 10 had partial regression, and a single patient had total regression. Minor complications such as perilesional edema, facial paresthesia, facial paralysis, and transient alopecia were observed in eight of the patients. Conclusions Patients with extra-axial, low-grade malignancy, and posterior fossa lesions were predominant in the studied population. Radiosurgery treatment is associated with good local control of the treated lesions. Complications are infrequent, mild, and predominated by perilesional edema.
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Fatty acids (FAs) are essential components of the central nervous system (CNS), where they exert multiple roles in health and disease. Among the FAs, docosahexaenoic acid (DHA) has been widely recognized as a key molecule for neuronal function and cell signaling. Despite its relevance, the molecular pathways underlying the beneficial effects of DHA on the cells of the CNS are still unclear. Here, we summarize and discuss the molecular mechanisms underlying the actions of DHA in neural cells with a special focus on processes of survival, morphological development, and synaptic maturation. In addition, we examine the evidence supporting a potential therapeutic role of DHA against CNS tumor diseases and tumorigenesis. The current results suggest that DHA exerts its actions on neural cells mainly through the modulation of signaling cascades involving the activation of diverse types of receptors. In addition, we found evidence connecting brain DHA and ω-3 PUFA levels with CNS diseases, such as depression, autism spectrum disorders, obesity, and neurodegenerative diseases. In the context of cancer, the existing data have shown that DHA exerts positive actions as a coadjuvant in antitumoral therapy. Although many questions in the field remain only partially resolved, we hope that future research may soon define specific pathways and receptor systems involved in the beneficial effects of DHA in cells of the CNS, opening new avenues for innovative therapeutic strategies for CNS diseases.
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Doenças do Sistema Nervoso Central , Ácidos Graxos Ômega-3 , Encéfalo/metabolismo , Sistema Nervoso Central/metabolismo , Doenças do Sistema Nervoso Central/tratamento farmacológico , Doenças do Sistema Nervoso Central/metabolismo , Ácidos Docosa-Hexaenoicos/metabolismo , Ácidos Docosa-Hexaenoicos/farmacologia , Ácidos Graxos/metabolismo , Ácidos Graxos Ômega-3/metabolismo , HumanosRESUMO
The Zika virus (ZIKV) has shown a promising oncolytic effect against embryonal CNS tumors. However, studies on the effect of different administration routes and the ideal viral load in preclinical models are highly relevant aiming for treatment safety and efficiency. Here, we investigated the effect and effectiveness of different routes of administration, and the number of ZIKVBR injections on tumor tropism, destruction, and side effects. Furthermore, we designed an early-stage human brain organoid co-cultured with embryonal CNS tumors to analyze the ZIKVBR oncolytic effect. We showed that in the mice bearing subcutaneous tumors, the ZIKVBR systemically presented a tropism to the brain. When the tumor was located in the mice's brain, serial systemic injections presented efficient tumor destruction, with no neurological or other organ injury and increased mice survival. In the human cerebral organoid model co-cultured with embryonal CNS tumor cells, ZIKVBR impaired tumor progression. The gene expression of cytokines and chemokines in both models suggested an enhancement of immune cells recruitment and tumor inflammation after the treatment. These results open new perspectives for virotherapy using the ZIKVBR systemic administration route and multiple doses of low virus load for safe and effective treatment of embryonal CNS tumors, an orphan disease that urges new effective therapies.
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Neoplasias Encefálicas/terapia , Terapia Viral Oncolítica/métodos , Zika virus/metabolismo , Animais , Encéfalo/virologia , Neoplasias Encefálicas/patologia , Linhagem Celular , Sistema Nervoso Central/efeitos dos fármacos , Técnicas de Cocultura , Modelos Animais de Doenças , Humanos , Imunoterapia/métodos , Injeções Intralesionais/métodos , Camundongos , Camundongos Endogâmicos BALB C , Modelos Biológicos , Vírus Oncolíticos/metabolismo , Organoides , Zika virus/imunologia , Infecção por Zika virus/virologiaRESUMO
There is no evidence that prolonged pre diagnostic symptomatic intervals (PSI) increases the risk of death in pediatric brain tumors. When investigating the role of time previous research had not controlled for confounding variables or measured the pretreatment interval (PTI). We use the term global delay interval (GDI) to describe the sum of PSI and PTI. The aim of this research was to evaluate whether there was a decrease in the probability of survival in children with brain tumors due to a prolonged PSI, PTI and GDI, using a multivariate survival analysis. We retrospective review 127 clinical records labeled with the diagnosis of CNS tumors attended at a specialized pediatric center in Mexico City from January 2008 to December 2012. Patients with PSI and GDI diagnosed between 3 and 6 months showed statistical lower probability of surviving that those with intervals <3 months even when adjusting for age, sex, localization and tumor grade. When stratified for the place of residency and adjusted for sex, age, localization, grade of tumor, type of surgery and coadjuvant therapy, a GDI between 3 and 6 months showed to be a risk factor for the overall survival of brain tumors compared with an interval < 3 months. When analyzing the interaction, high grade tumors are at more risk of dying when GDI was between 3 and 6 months compared to <3 months. Prolonged PSI and GDI showed to be a potential prognostic factor for survival in CNS tumors, especially in high grade tumors. Future prospective research should measure the PSI, PTI and GDI and adjust for covariates in order to properly infer the effect of time in pediatric brain tumors.
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Neoplasias Encefálicas/mortalidade , Diagnóstico Tardio/estatística & dados numéricos , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Criança , Pré-Escolar , Terapia Combinada , Feminino , Seguimentos , Humanos , Masculino , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Fatores de TempoRESUMO
Malignant brain tumors are among the most aggressive cancers with poor prognosis and no effective treatment. Recently, we reported the oncolytic potential of Zika virus infecting and destroying the human central nervous system (CNS) tumors in vitro and in immunodeficient mice model. However, translating this approach to humans requires pre-clinical trials in another immunocompetent animal model. Here, we analyzed the safety of Brazilian Zika virus (ZIKVBR) intrathecal injections in three dogs bearing spontaneous CNS tumors aiming an anti-tumoral therapy. We further assessed some aspects of the innate immune and inflammatory response that triggers the anti-tumoral response observed during the ZIKVBR administration in vivo and in vitro. For the first time, we showed that there were no negative clinical side effects following ZIKVBR CNS injections in dogs, confirming the safety of the procedure. Furthermore, the intrathecal ZIKVBR injections reduced tumor size in immunocompetent dogs bearing spontaneous intracranial tumors, improved their neurological clinical symptoms significantly, and extended their survival by inducing the destruction specifically of tumor cells, sparing normal neurons, and activating an immune response. These results open new perspectives for upcoming virotherapy using ZIKV to destroy and induce an anti-tumoral immune response in CNS tumors for which there are currently no effective treatments.
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Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/terapia , Terapia Viral Oncolítica/métodos , Segurança do Paciente , Carga Tumoral , Infecção por Zika virus/complicações , Zika virus/imunologia , Animais , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Técnicas de Cocultura , Citocinas/metabolismo , Modelos Animais de Doenças , Cães , Imunidade , Injeções Espinhais , Masculino , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/virologia , Monócitos/imunologia , Monócitos/virologia , Neurônios/metabolismo , Neurônios/virologia , Resultado do TratamentoRESUMO
Malignant brain tumors are among the most aggressive cancers with poor prognosis and no effective treatment. Recently, we reported the oncolytic potential of Zika virus infecting and destroying the human central nervous system (CNS) tumors in vitro and in immunodeficient mice model. However, translating this approach to humans requires pre-clinical trials in another immunocompetent animal model. Here, we analyzed the safety of Brazilian Zika virus (ZIKVBR) intrathecal injections in three dogs bearing spontaneous CNS tumors aiming an anti-tumoral therapy. We further assessed some aspects of the innate immune and inflammatory response that triggers the anti-tumoral response observed during the ZIKVBR administration in vivo and in vitro. For the first time, we showed that there were no negative clinical side effects following ZIKVBR CNS injections in dogs, confirming the safety of the procedure. Furthermore, the intrathecal ZIKVBR injections reduced tumor size in immunocompetent dogs bearing spontaneous intracranial tumors, improved their neurological clinical symptoms significantly, and extended their survival by inducing the destruction specifically of tumor cells, sparing normal neurons, and activating an immune response. These results open new perspectives for upcoming virotherapy using ZIKV to destroy and induce an anti-tumoral immune response in CNS tumors for which there are currently no effective treatments.
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PURPOSE: Elevated mortality and morbidity rates persist in pediatric patients with medulloblastoma. We present a clinical audit of a real-world cohort of patients in search for pragmatic measures to improve their management and outcome. METHODS/PATIENTS: All pediatric patients with medulloblastoma treated between 2003 and 2016 at a Spanish reference center were reviewed. In the absence of internationally accepted quality indicators (QIs) for pediatric CNS tumors, diagnostic, therapeutic, survival, and time QIs were defined and assessed. RESULTS: Fifty-eight patients were included, 24% were younger children (< 3 years), 36% high risk (anaplastic, metastasis, or surgical residue > 1.5 cm2), and 40% standard risk. Five-year OS was 59.2% (95% CI 47-75); 5-year PFS 36.4% (95% CI 25-53). Five main areas of quality assurance were identified: diagnosis, global strategy, frontline treatment modalities, outcomes, and long-term and end-of-life care. A set of 34 QIs was developed and applied. Lack of central pathology review, delay in the incorporation of novel molecular markers, and absence of a neurocognitive and quality-of-life evaluation program were some of the audit findings. CONCLUSIONS: This real-world research study resulted in the development of a pragmatic set of QIs, aimed to improve clinical audits and quality of care given to children and adolescents with medulloblastoma. We hope that our findings will serve as a reference to further develop a quality assurance system with specific QIs for pediatric CNS tumors in the future and that this will ultimately improve the survival and quality of life of these patients.
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Neoplasias Cerebelares/terapia , Meduloblastoma/terapia , Qualidade da Assistência à Saúde , Adolescente , Criança , Pré-Escolar , Feminino , Hospitais Pediátricos/estatística & dados numéricos , Humanos , Lactente , Masculino , Recidiva Local de Neoplasia , Prognóstico , Intervalo Livre de Progressão , Garantia da Qualidade dos Cuidados de Saúde , Espanha , Resultado do TratamentoRESUMO
INTRODUCTION: Pediatric central nervous system tumors are one of the most frequent types of neoplasms in children but epidemiological data on these tumors have been sparsely reported in the medical literature. MATERIALS AND METHODS: We analyze the epidemiology of this type of tumors performing a retrospective population-based study in pediatrics and adolescent age in the population of Girona and compare them with series from Spain, Europe and worldwide. Cases were registered using the International Classification of Disease for Oncology, third edition and grouping according the International Classification of Childhood Cancer, third edition (ICCC-3). RESULTS: For all the histologies and the whole population between 0 and 19 years old, ASRw was 41.8 cases per million person-years. In children population, meaning under 14 years old, we found 104 cases with ASRw of 45.6. Males were the most affected by CNS tumors with a 1.2 sex ratio between 0 and 14 years old, and 1.1 between 0 and 19 years old. The analysis of trends in incidence did not find any statistically significant increase or decrease. Five-year observed survival was 68%, both for patients under 19 and 14 years of age. CONCLUSIONS: The incidence in our area was among the highest in Spain and worldwide, while survival was comparable to others reported.
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Neoplasias do Sistema Nervoso Central/epidemiologia , Neoplasias do Sistema Nervoso Central/mortalidade , Sistema de Registros/estatística & dados numéricos , Adolescente , Adulto , Fatores Etários , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Incidência , Lactente , Recém-Nascido , Agências Internacionais , Masculino , Prognóstico , Estudos Retrospectivos , Espanha/epidemiologia , Taxa de Sobrevida , Fatores de Tempo , Adulto JovemRESUMO
Background: Cancers of the brain and CNS constitute a group of rare and heterogeneous tumors. Increasing incidence in Western populations has been linked to improvements in diagnostic technology, although interpretation is hampered by changes in diagnosis and reporting. The present study examines geographic and temporal variations in incidence rates of brain and CNS cancers worldwide. Methods: Data from successive volumes of Cancer Incidence in Five Continents were used, including 96 registries in 39 countries. We used Joinpoint regression to estimate the average annual percentage change and its 95% CI. Results: Globally, a large variability in the magnitude of the diagnosis of new cases of brain and CNS cancer was found, with a 5-fold difference between the highest rates (mainly in Europe) and the lowest (mainly in Asia). Increasing rates of brain and CNS cancer were found in South America, namely in Ecuador, Brazil, and Colombia; in eastern Europe (Czech Republic and Russia), in southern Europe (Slovenia), and in the 3 Baltic countries. Trends were similar between sexes, although decreasing trends in men and women were seen in Japan and New Zealand. Conclusions: Important regional variations in brain and CNS cancers exist, and given an increasing burden and risk worldwide, there is a need for further etiological research that focuses on the elucidation of environmental risk. The trends are sufficiently complex and diffuse, however, to warrant a cautious approach to interpretation.
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Neoplasias Encefálicas/epidemiologia , Neoplasias do Sistema Nervoso Central/epidemiologia , Saúde Global , Sistema de Registros/estatística & dados numéricos , Adulto , África/epidemiologia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , América/epidemiologia , Ásia/epidemiologia , Europa (Continente)/epidemiologia , Feminino , Humanos , Incidência , Agências Internacionais , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Oceania/epidemiologia , Prognóstico , Fatores Sexuais , Taxa de Sobrevida , Fatores de TempoRESUMO
Several markers have been studied for their ability to make the CNS infiltration diagnosis earlier and more precise; previous studies showed that CSF ferritin concentrations were higher in patients with malignant invasion of CNS. The objective was to determine the importance of CSF ferritin as a biomarker for the diagnosis of CNS neoplasic infiltration. This study is based on 93 CSF samples, divided into five groups: malignant cells present (n13); malignant cells not present (n26); inflammatory neurological diseases (n16); neurocysticercosis (n20); acute bacterial meningitis (n18). CSF ferritin values were determined by micro particle enzyme immunoassay. CSF ferritin level (mean±SD) in the group with neoplasic cells in the CSF was 42.8±49.7 ng /mL, higher than in the other groups (p<0.0001). We conclude that CSF ferritin with the cut off 20 ng/mL could be an adjuvant biomarker to the diagnosis of CNS malignant infiltration.
Diversos marcadores foram estudados com a finalidade de avaliar sua capacidade de diagnosticar a infiltração neoplásica no SNC precocemente e de forma mais precisa. Estudos anteriores mostraram que as concentrações de ferritina no LCR eram mais elevadas nos pacientes com infiltração neoplásica no SNC. O objetivo foi determinar a importância da ferritina no LCR como biomarcador para o diagnóstico de infiltração neoplásica no SNC. Este estudo é baseado em 93 amostras do LCR, divididas em cinco grupos: células malignas presentes (n13); células malignas ausentes (n26); doenças neurologicas inflamatórias (n16); neurocisticercose (n20); meningites bacterianas agudas (n18). Os valores de ferritina no LCR foram determinados por ELISA de microparticulas. O nível de ferritina no LCR (média±desvio padrão) no grupo com células neoplásicas no LCR foi 42,8±49,7 ng/mL, mais elevado do que nos outros grupos (p<0.0001). Concluímos que a ferritina no LCR com cut off de 20 ng/mL pode ser um biomarcador para o diagnóstico de infiltração maligna no SNC.
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Humanos , Neoplasias do Sistema Nervoso Central/líquido cefalorraquidiano , Ferritinas/líquido cefalorraquidiano , Biomarcadores Tumorais/líquido cefalorraquidiano , Neoplasias do Sistema Nervoso Central/diagnóstico , Ensaio de Imunoadsorção Enzimática , Sensibilidade e EspecificidadeRESUMO
Central nervous system (CNS) infiltration must be ruled out in patients with known neoplastic diseases and neurological symptoms. It was done a retrospective analysis of 1,948 CSF samples from patients with suspected malignant infiltration in the CNS, in order to evaluate the positivity rate of malignant cells in cerebrospinal fluid (CSF) samples and correlate with cytochemical characteristics. Sixty-two percent of subjects had acute lymphocytic leukemia. Malignant cells were found in 24 percent of all CSF samples. Subjects with positive malignant cells had predominance of increased levels of CSF total protein (TP), glucose and total cytology (p<0.05). Mean total cell count in this group was 232 (SD 933) cells/mm³, compared to 9 (SD 93) cells/mm³ in the group without neoplasic cells (p=0.029). CSF TP specificity was 87 percent and negative predictive value (NPV) 96 percent. CSF total cell count specificity 86 percent and NPV 97 percent. Although sensitivity and positive predictive value were low. The presence of inflammatory cells and elevated TP found in patients with malignant cells in the CSF can aid in diagnosing CNS neoplasms.
A infiltração neoplásica no SNC deve ser afastada em pacientes com neoplasia e sintomas neurológicos. Foi realizada uma análise retrospectiva de 1.948 amostras de LCR de pacientes com suspeita de infiltração neoplásica no SNC. Sessenta e dois por cento dos pacientes eram portadores de leucemia linfocitica aguda. Células neoplásicas foram encontradas em 24 por cento de todas as amostras. Houve níveis aumentados no LCR da proteína total (PT), glicose e de citologia global (p<0.05), no grupo com presença de células neoplásicas. A média da contagem global de células no LCR, neste grupo, foi 232±933 cels/mm³, contra 9±93 cells/mm³ no grupo sem células neoplásicas no LCR (p=0,029). O aumento de PT no LCR apresentou especificidade 87 por cento e valor preditivo negativo (VPN) 96 por cento. A contagem global de células no LCR apresentou especificidade 86 por cento e VPN 97 por cento. Porém sensibilidade e valores preditivos positivos foram baixos. A presença de células inflamatórias e PT no LCR elevada em pacientes com neoplasias pode ser um indicador do envolvimento no SNC.
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Adolescente , Feminino , Humanos , Masculino , Neoplasias do Sistema Nervoso Central/líquido cefalorraquidiano , Líquido Cefalorraquidiano/química , Líquido Cefalorraquidiano/citologia , Estudos Longitudinais , Valor Preditivo dos Testes , Estudos Retrospectivos , Sensibilidade e Especificidade , Biomarcadores Tumorais/líquido cefalorraquidianoRESUMO
Se sabe que el tratamiento de los tumores del sistema nervioso central (SNC) está basado en el empleo de la cirugía y la radioterapia (RT) y que la quimioterapia (QMT) se emplea cada vez más, así como los otros medicamentos. Se hizo una revisión bibliográfica para actualizar los conocimientos sobre las tendencias actuales y perspectivas de la RT aplicada a los tumores del SNC, entre las cuales se hallan: a) combinaciones de RT y QMT; b) radiosensibilizadores incorporados al tratamiento radiante; c) inhibidores de la angiogénesis asociados a la RT; d) la escalada o incremento de las dosis de RT, gracias al desarrollo de nuevas tecnologías como la radioterapia conformacional en tercera dimensión, la radioterapia de intensidad modulada, la cirugía y otros; otro campo de investigación es el constituido por los cambios en el ritmo o fraccionamiento de la RT: hiperfraccionada, acelerada, combinaciones de ambas, etc., lo que permitirá principalmente incrementar el escalado de las dosis.
It is known that the treatment of the central nervous system (CNS) tumors is based on the use of surgery and radiotherapy (RT) and that chemotherapy (QMT) is used even more, as well as the other drugs. A bibliographic review was made to update the knowledge on the current trends and perspectives of RT applied to CNS tumors. The following were found among them: a) combinations of RT and CMT; b) radiosensibilizers incorporated to the radiant treatment; c) angiogenesis inhibitors associated with RT; d) the scale-up or increase of the RT doses thanks to the development of new technologies, such as 3 D conformal radiotherapy, intensity- modulated radiotherapy, surgery and others. Another field of research is that of the changes in the rhythm or fractioning of the RT: hyperfractionated, accelerated, combinations of both, etc., which will allow mainly to increase the dosage scale-up.