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1.
Artigo em Inglês | MEDLINE | ID: mdl-31381960

RESUMO

PURPOSE AND METHODS: The advent of affordable and rapid next-generation DNA sequencing technology, along with the US Supreme Court ruling invalidating gene patents, has led to a deluge of germline and tumor genetic variant tests that are being rapidly incorporated into clinical cancer decision making. A major concern for clinicians is whether the presence of germline mutations may increase the risk of radiation toxicity or secondary malignancies. Since minimal clinical data exist to inform decisions at this time, the American Society for Radiation Oncology (ASTRO) convened a group of radiation science experts and clinicians to summarize potential issues, review relevant data, and provide guidance for adult patients and their care teams regarding the impact, if any, that genetic testing should have on radiation therapy recommendations. RESULTS AND CONCLUSIONS: During the ASTRO Workshop, several main points emerged, which are discussed in this manuscript: 1) Variants of uncertain significance should be considered non-deleterious until functional genomic data emerges to demonstrate otherwise; 2) Possession of germline alterations in a single copy of a gene critical for radiation damage responses does not necessarily equate to increased risk of radiation-induced toxicity; 3) Deleterious ATM mutations may modestly increase second cancer risk after radiotherapy, thus follow-up for these patients after indicated radiotherapy should include second cancer screening; 4) Conveying to patients the difference between relative and absolute risk is critical to decision making; and 5) More work is needed to assess the impact of tumor somatic alterations on the probability of response to radiotherapy and the potential for individualization of radiation doses. Data on radiosensitivity related to specific genetic mutations is also briefly discussed.

3.
J Natl Cancer Inst ; 2019 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-31095341

RESUMO

BACKGROUND: 10-20% of patients develop long-term toxicity following radiotherapy for prostate cancer. Identification of common genetic variants associated with susceptibility to radiotoxicity might improve risk prediction and inform functional mechanistic studies. METHODS: We conducted an individual patient data meta-analysis of six genome-wide association studies (n = 3,871) in men with European ancestry who underwent radiotherapy for prostate cancer. Radiotoxicities (increased urinary frequency, decreased urinary stream, hematuria, rectal bleeding) were graded prospectively. Grouped relative risk models tested associations with ∼6 million genotyped/imputed variants (time to first ≥grade 2 toxicity event). Variants with two-sided Pmeta<5x10-8 were considered statistically significant. Bayesian false discovery probability provided an additional measure of confidence. Statistically significant variants were evaluated in three Japanese cohorts (n = 962). All statistical tests were two-sided. RESULTS: Meta-analysis of the European ancestry cohorts identified three genomic signals: single nucleotide polymorphism (SNP) rs17055178 with rectal bleeding (Pmeta=6.2x10-10), rs10969913 with decreased urinary stream (Pmeta=2.9x10-10) and rs11122573 with hematuria (Pmeta=1.8x10-8). Fine scale mapping of these three regions identified another independent signal (rs147121532) associated with hematuria (Pconditional=4.7x10-6). Credible causal variants at these four signals lie in gene-regulatory regions, some modulating expression of nearby genes. Previously identified variants showed consistent associations (rs17599026 with increased urinary frequency, rs7720298 with decreased urinary stream, rs1801516 with overall toxicity) in new cohorts. rs10969913 and rs17599026 had similar effects in the photon-treated Japanese cohorts. CONCLUSIONS: This study increases understanding of the architecture of common genetic variants affecting radiotoxicity, points to novel radio-pathogenic mechanisms, and develops risk models for testing in clinical studies. Further multi-national radiogenomics studies in larger cohorts are worthwhile.

4.
Radiother Oncol ; 138: 59-67, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31146072

RESUMO

PURPOSE: REQUITE aimed to establish a resource for multi-national validation of models and biomarkers that predict risk of late toxicity following radiotherapy. The purpose of this article is to provide summary descriptive data. METHODS: An international, prospective cohort study recruited cancer patients in 26 hospitals in eight countries between April 2014 and March 2017. Target recruitment was 5300 patients. Eligible patients had breast, prostate or lung cancer and planned potentially curable radiotherapy. Radiotherapy was prescribed according to local regimens, but centres used standardised data collection forms. Pre-treatment blood samples were collected. Patients were followed for a minimum of 12 (lung) or 24 (breast/prostate) months and summary descriptive statistics were generated. RESULTS: The study recruited 2069 breast (99% of target), 1808 prostate (86%) and 561 lung (51%) cancer patients. The centralised, accessible database includes: physician- (47,025 forms) and patient- (54,901) reported outcomes; 11,563 breast photos; 17,107 DICOMs and 12,684 DVHs. Imputed genotype data are available for 4223 patients with European ancestry (1948 breast, 1728 prostate, 547 lung). Radiation-induced lymphocyte apoptosis (RILA) assay data are available for 1319 patients. DNA (n = 4409) and PAXgene tubes (n = 3039) are stored in the centralised biobank. Example prevalences of 2-year (1-year for lung) grade ≥2 CTCAE toxicities are 13% atrophy (breast), 3% rectal bleeding (prostate) and 27% dyspnoea (lung). CONCLUSION: The comprehensive centralised database and linked biobank is a valuable resource for the radiotherapy community for validating predictive models and biomarkers. PATIENT SUMMARY: Up to half of cancer patients undergo radiation therapy and irradiation of surrounding healthy tissue is unavoidable. Damage to healthy tissue can affect short- and long-term quality-of-life. Not all patients are equally sensitive to radiation "damage" but it is not possible at the moment to identify those who are. REQUITE was established with the aim of trying to understand more about how we could predict radiation sensitivity. The purpose of this paper is to provide an overview and summary of the data and material available. In the REQUITE study 4400 breast, prostate and lung cancer patients filled out questionnaires and donated blood. A large amount of data was collected in the same way. With all these data and samples a database and biobank were created that showed it is possible to collect this kind of information in a standardised way across countries. In the future, our database and linked biobank will be a resource for research and validation of clinical predictors and models of radiation sensitivity. REQUITE will also enable a better understanding of how many people suffer with radiotherapy toxicity.

5.
Int J Part Ther ; 5(1): 103-113, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30505881

RESUMO

Radiogenomics is the study of genomic factors that are associated with response to radiation therapy. In recent years, progress has been made toward identifying genetic risk factors linked with late radiation-induced adverse effects. These advances have been underpinned by the establishment of an international Radiogenomics Consortium with collaborative studies that expand cohort sizes to increase statistical power and efforts to improve methodologic approaches for radiogenomic research. Published studies have predominantly reported the results of research involving patients treated with photons using external beam radiation therapy. These studies demonstrate our ability to pool international cohorts to identify common single nucleotide polymorphisms associated with risk for developing normal tissue toxicities. Progress has also been achieved toward the discovery of genetic variants associated with radiation therapy-related subsequent malignancies. With the increasing use of charged particle therapy (CPT), there is a need to establish cohorts for patients treated with these advanced technology forms of radiation therapy and to create biorepositories with linked clinical data. While some genetic variants are likely to impact toxicity and second malignancy risks for both photons and charged particles, it is plausible that others may be specific to the radiation modality due to differences in their biological effects, including the complexity of DNA damage produced. In recognition that the formation of patient cohorts treated with CPT for radiogenomic studies is a high priority, efforts are underway to establish collaborations involving institutions treating cancer patients with protons and/or carbon ions as well as consortia, including the Proton Collaborative Group, the Particle Therapy Cooperative Group, and the Pediatric Proton Consortium Registry. These important radiogenomic CPT initiatives need to be expanded internationally to build on experience gained from the Radiogenomics Consortium and epidemiologists investigating normal tissue toxicities and second cancer risk.

6.
Artigo em Inglês | MEDLINE | ID: mdl-30352818

RESUMO

BACKGROUND: Whether associations between circulating metabolites and prostate cancer are causal is unknown. We report on the largest study of metabolites and prostate cancer (2,291 cases and 2,661 controls) and appraise causality for a subset of the prostate cancer-metabolite associations using two-sample Mendelian randomization (MR). MATERIALS AND METHODS: The case-control portion of the study was conducted in nine UK centres with men aged 50-69 years who underwent prostate-specific antigen (PSA) screening for prostate cancer within the Prostate testing for cancer and Treatment (ProtecT) trial. Two data sources were used to appraise causality: a genome-wide association study (GWAS) of metabolites in 24,925 participants and a GWAS of prostate cancer in 44,825 cases and 27,904 controls within the Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. RESULTS: Thirty-five metabolites were strongly associated with prostate cancer (p <0.0014, multiple-testing threshold). These fell into four classes: i) lipids and lipoprotein subclass characteristics (total cholesterol and ratios, cholesterol esters and ratios, free cholesterol and ratios, phospholipids and ratios, and triglyceride ratios); ii) fatty acids and ratios; iii) amino acids; iv) and fluid balance. Fourteen top metabolites were proxied by genetic variables, but MR indicated these were not causal. CONCLUSIONS: We identified 35 circulating metabolites associated with prostate cancer presence, but found no evidence of causality for those 14 testable with MR. Thus, the 14 MR-tested metabolites are unlikely to be mechanistically important in prostate cancer risk. IMPACT: The metabolome provides a promising set of biomarkers that may aid prostate cancer classification.

8.
Front Oncol ; 8: 228, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29977864

RESUMO

Due to the rapid increase in the availability of patient data, there is significant interest in precision medicine that could facilitate the development of a personalized treatment plan for each patient on an individual basis. Radiation oncology is particularly suited for predictive machine learning (ML) models due to the enormous amount of diagnostic data used as input and therapeutic data generated as output. An emerging field in precision radiation oncology that can take advantage of ML approaches is radiogenomics, which is the study of the impact of genomic variations on the sensitivity of normal and tumor tissue to radiation. Currently, patients undergoing radiotherapy are treated using uniform dose constraints specific to the tumor and surrounding normal tissues. This is suboptimal in many ways. First, the dose that can be delivered to the target volume may be insufficient for control but is constrained by the surrounding normal tissue, as dose escalation can lead to significant morbidity and rare. Second, two patients with nearly identical dose distributions can have substantially different acute and late toxicities, resulting in lengthy treatment breaks and suboptimal control, or chronic morbidities leading to poor quality of life. Despite significant advances in radiogenomics, the magnitude of the genetic contribution to radiation response far exceeds our current understanding of individual risk variants. In the field of genomics, ML methods are being used to extract harder-to-detect knowledge, but these methods have yet to fully penetrate radiogenomics. Hence, the goal of this publication is to provide an overview of ML as it applies to radiogenomics. We begin with a brief history of radiogenomics and its relationship to precision medicine. We then introduce ML and compare it to statistical hypothesis testing to reflect on shared lessons and to avoid common pitfalls. Current ML approaches to genome-wide association studies are examined. The application of ML specifically to radiogenomics is next presented. We end with important lessons for the proper integration of ML into radiogenomics.

9.
Semin Radiat Oncol ; 27(4): 300-309, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28865512

RESUMO

The overall goal of radiogenomics is the identification of genomic markers that are predictive for the development of adverse effects resulting from cancer treatment with radiation. The principal rationale for a focus on toxicity in radiogenomics is that for many patients treated with radiation, especially individuals diagnosed with early-stage cancers, the survival rates are high, and therefore a substantial number of people will live for a significant period of time beyond treatment. However, many of these patients could suffer from debilitating complications resulting from radiotherapy. Work in radiogenomics has greatly benefited from creation of the Radiogenomics Consortium (RGC) that includes investigators at multiple institutions located in a variety of countries. The common goal of the RGC membership is to share biospecimens and data so as to achieve large-scale studies with increased statistical power to enable identification of relevant genomic markers. A major aim of research in radiogenomics is the development of a predictive instrument to enable identification of people who are at greatest risk for adverse effects resulting from cancer treatment using radiation. It is anticipated that creation of a predictive assay characterized by a high level of sensitivity and specificity will improve precision radiotherapy and assist patients and their physicians to select the optimal treatment for each individual.


Assuntos
Genômica/métodos , Neoplasias/radioterapia , Lesões por Radiação/genética , Marcadores Genéticos , Genômica/organização & administração , Humanos , Neoplasias/genética
10.
Phys Med Biol ; 62(16): R179-R206, 2017 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-28657906

RESUMO

Advances in patient-specific information and biotechnology have contributed to a new era of computational medicine. Radiogenomics has emerged as a new field that investigates the role of genetics in treatment response to radiation therapy. Radiation oncology is currently attempting to embrace these recent advances and add to its rich history by maintaining its prominent role as a quantitative leader in oncologic response modeling. Here, we provide an overview of radiogenomics starting with genotyping, data aggregation, and application of different modeling approaches based on modifying traditional radiobiological methods or application of advanced machine learning techniques. We highlight the current status and potential for this new field to reshape the landscape of outcome modeling in radiotherapy and drive future advances in computational oncology.


Assuntos
Genômica/métodos , Modelos Biológicos , Neoplasias/genética , Neoplasias/radioterapia , Humanos , Radiobiologia , Resultado do Tratamento
11.
Front Oncol ; 7: 83, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28497027

RESUMO

The ability to stratify patients using a set of biomarkers, which predict that toxicity risk would allow for radiotherapy (RT) modulation and serve as a valuable tool for precision medicine and personalized RT. For patients presenting with tumors with a low risk of recurrence, modifying RT schedules to avoid toxicity would be clinically advantageous. Indeed, for the patient at low risk of developing radiation-associated toxicity, use of a hypofractionated protocol could be proposed leading to treatment time reduction and a cost-utility advantage. Conversely, for patients predicted to be at high risk for toxicity, either a more conformal form or a new technique of RT, or a multidisciplinary approach employing surgery could be included in the trial design to avoid or mitigate RT when the potential toxicity risk may be higher than the risk of disease recurrence. In addition, for patients at high risk of recurrence and low risk of toxicity, dose escalation, such as a greater boost dose, or irradiation field extensions could be considered to improve local control without severe toxicities, providing enhanced clinical benefit. In cases of high risk of toxicity, tumor control should be prioritized. In this review, toxicity biomarkers with sufficient evidence for clinical testing are presented. In addition, clinical trial designs and predictive models are described for different clinical situations.

12.
EBioMedicine ; 10: 150-63, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27515689

RESUMO

Nearly 50% of cancer patients undergo radiotherapy. Late radiotherapy toxicity affects quality-of-life in long-term cancer survivors and risk of side-effects in a minority limits doses prescribed to the majority of patients. Development of a test predicting risk of toxicity could benefit many cancer patients. We aimed to meta-analyze individual level data from four genome-wide association studies from prostate cancer radiotherapy cohorts including 1564 men to identify genetic markers of toxicity. Prospectively assessed two-year toxicity endpoints (urinary frequency, decreased urine stream, rectal bleeding, overall toxicity) and single nucleotide polymorphism (SNP) associations were tested using multivariable regression, adjusting for clinical and patient-related risk factors. A fixed-effects meta-analysis identified two SNPs: rs17599026 on 5q31.2 with urinary frequency (odds ratio [OR] 3.12, 95% confidence interval [CI] 2.08-4.69, p-value 4.16×10(-8)) and rs7720298 on 5p15.2 with decreased urine stream (OR 2.71, 95% CI 1.90-3.86, p-value=3.21×10(-8)). These SNPs lie within genes that are expressed in tissues adversely affected by pelvic radiotherapy including bladder, kidney, rectum and small intestine. The results show that heterogeneous radiotherapy cohorts can be combined to identify new moderate-penetrance genetic variants associated with radiotherapy toxicity. The work provides a basis for larger collaborative efforts to identify enough variants for a future test involving polygenic risk profiling.


Assuntos
Marcadores Genéticos , Estudo de Associação Genômica Ampla , Neoplasias da Próstata/genética , Tolerância a Radiação/genética , Radioterapia/efeitos adversos , Idoso , Alelos , Estudos de Coortes , Terapia Combinada , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Razão de Chances , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/patologia , Neoplasias da Próstata/radioterapia , Qualidade de Vida , Resultado do Tratamento
13.
Radiother Oncol ; 121(3): 431-439, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27443449

RESUMO

PURPOSE: Several small studies have indicated that the ATM rs1801516 SNP is associated with risk of normal tissue toxicity after radiotherapy. However, the findings have not been consistent. In order to test this SNP in a well-powered study, an individual patient data meta-analysis was carried out by the International Radiogenomics Consortium. MATERIALS AND METHODS: The analysis included 5456 patients from 17 different cohorts. 2759 patients were given radiotherapy for breast cancer and 2697 for prostate cancer. Eight toxicity scores (overall toxicity, acute toxicity, late toxicity, acute skin toxicity, acute rectal toxicity, telangiectasia, fibrosis and late rectal toxicity) were analyzed. Adjustments were made for treatment and patient related factors with potential impact on the risk of toxicity. RESULTS: For all endpoints except late rectal toxicity, a significantly increased risk of toxicity was found for carriers of the minor (Asn) allele with odds ratios of approximately 1.5 for acute toxicity and 1.2 for late toxicity. The results were consistent with a co-dominant pattern of inheritance. CONCLUSION: This study convincingly showed a significant association between the ATM rs1801516 Asn allele and increased risk of radiation-induced normal tissue toxicity.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Neoplasias da Mama/radioterapia , Neoplasias da Próstata/radioterapia , Lesões por Radiação/genética , Alelos , Neoplasias da Mama/genética , Feminino , Predisposição Genética para Doença , Genótipo , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/genética , Lesões por Radiação/etiologia , Tolerância a Radiação/genética , Radioterapia/efeitos adversos , Fatores de Risco
15.
Int J Radiat Oncol Biol Phys ; 95(2): 571-8, 2016 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-27131077

RESUMO

PURPOSE: To report the results of a prospective randomized trial comparing a daily versus weekly boost to the tumor cavity during the course of accelerated radiation to the breast with patients in the prone position. METHODS AND MATERIALS: From 2009 to 2012, 400 patients with stage 0 to II breast cancer who had undergone segmental mastectomy participated in an institutional review board-approved trial testing prone breast radiation therapy to 40.5 Gy in 15 fractions 5 d/wk to the whole breast, after randomization to a concomitant daily boost to the tumor bed of 0.5 Gy, or a weekly boost of 2 Gy, on Friday. The present noninferiority trial tested the primary hypothesis that a weekly boost produced no more acute toxicity than did a daily boost. The recurrence-free survival was estimated for both treatment arms using the Kaplan-Meier method; the relative risk of recurrence or death was estimated, and the 2 arms were compared using the log-rank test. RESULTS: At a median follow-up period of 45 months, no deaths related to breast cancer had occurred. The weekly boost regimen produced no more grade ≥2 acute toxicity than did the daily boost regimen (8.1% vs 10.4%; noninferiority Z = -2.52; P=.006). No statistically significant difference was found in the cumulative incidence of long-term fibrosis or telangiectasia of grade ≥2 between the 2 arms (log-rank P=.923). Two local and two distant recurrences developed in the daily treatment arm and three local and one distant developed in the weekly arm. The 4-year recurrence-free survival rate was not different between the 2 treatment arms (98% for both arms). CONCLUSIONS: A tumor bed boost delivered either daily or weekly was tolerated similarly during accelerated prone breast radiation therapy, with excellent control of disease and comparable cosmetic results.


Assuntos
Neoplasias da Mama/radioterapia , Radioterapia de Intensidade Modulada/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/mortalidade , Fracionamento da Dose de Radiação , Feminino , Humanos , Pessoa de Meia-Idade , Decúbito Ventral , Estudos Prospectivos , Radioterapia de Intensidade Modulada/efeitos adversos
16.
Br J Cancer ; 114(10): 1165-74, 2016 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-27070714

RESUMO

BACKGROUND: Numerous germline single-nucleotide polymorphisms increase susceptibility to prostate cancer, some lying near genes involved in cellular radiation response. This study investigated whether prostate cancer patients with a high genetic risk have increased toxicity following radiotherapy. METHODS: The study included 1560 prostate cancer patients from four radiotherapy cohorts: RAPPER (n=533), RADIOGEN (n=597), GenePARE (n=290) and CCI (n=150). Data from genome-wide association studies were imputed with the 1000 Genomes reference panel. Individuals were genetically similar with a European ancestry based on principal component analysis. Genetic risks were quantified using polygenic risk scores. Regression models tested associations between risk scores and 2-year toxicity (overall, urinary frequency, decreased stream, rectal bleeding). Results were combined across studies using standard inverse-variance fixed effects meta-analysis methods. RESULTS: A total of 75 variants were genotyped/imputed successfully. Neither non-weighted nor weighted polygenic risk scores were associated with late radiation toxicity in individual studies (P>0.11) or after meta-analysis (P>0.24). No individual variant was associated with 2-year toxicity. CONCLUSION: Patients with a high polygenic susceptibility for prostate cancer have no increased risk for developing late radiotherapy toxicity. These findings suggest that patients with a genetic predisposition for prostate cancer, inferred by common variants, can be safely treated using current standard radiotherapy regimens.


Assuntos
Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/genética , Neoplasias da Próstata/radioterapia , Lesões por Radiação/epidemiologia , Idoso , Grupo com Ancestrais do Continente Europeu/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Mutação em Linhagem Germinativa , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Componente Principal , Neoplasias da Próstata/etnologia
17.
Cancer Lett ; 382(1): 95-109, 2016 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-26944314

RESUMO

Adverse reactions in normal tissue after radiotherapy (RT) limit the dose that can be given to tumour cells. Since 80% of individual variation in clinical response is estimated to be caused by patient-related factors, identifying these factors might allow prediction of patients with increased risk of developing severe reactions. While inactivation of cell renewal is considered a major cause of toxicity in early-reacting normal tissues, complex interactions involving multiple cell types, cytokines, and hypoxia seem important for late reactions. Here, we review 'omics' approaches such as screening of genetic polymorphisms or gene expression analysis, and assess the potential of epigenetic factors, posttranslational modification, signal transduction, and metabolism. Furthermore, functional assays have suggested possible associations with clinical risk of adverse reaction. Pathway analysis incorporating different 'omics' approaches may be more efficient in identifying critical pathways than pathway analysis based on single 'omics' data sets. Integrating these pathways with functional assays may be powerful in identifying multiple subgroups of RT patients characterised by different mechanisms. Thus 'omics' and functional approaches may synergise if they are integrated into radiogenomics 'systems biology' to facilitate the goal of individualised radiotherapy.


Assuntos
Polimorfismo de Nucleotídeo Único , Doses de Radiação , Exposição à Radiação/efeitos adversos , Lesões por Radiação/genética , Radioterapia/efeitos adversos , Biologia de Sistemas/métodos , Integração de Sistemas , Perfilação da Expressão Gênica , Marcadores Genéticos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genômica/métodos , Humanos , Fenótipo , Proteômica/métodos , Lesões por Radiação/metabolismo , Medição de Risco , Fatores de Risco
19.
PLoS One ; 10(10): e0139448, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26448647

RESUMO

PURPOSE/OBJECTIVES: We observed a number of patients who developed Lhermitte's sign (LS) following radiation to the head and neck (H/N), since instituting volumetric modulated arc therapy (VMAT). We aimed to investigate the incidence of LS following VMAT-based RT without chemotherapy, and determine the dosimetric parameters that predict its development. We explored whether the role of inhomogeneous dose distribution across the spinal cord, causing a "bath-and-shower" effect, explains this finding. METHODS AND MATERIALS: From 1/20/2010-12/9/2013, we identified 33 consecutive patients receiving adjuvant RT using VMAT to the H/N without chemotherapy at our institution. Patients' treatment plans were analyzed for dosimetric parameters, including dose gradients along the anterior, posterior, right, and left quadrants at each cervical spine level. Institutional Review Board approval was obtained. RESULTS: 5 out of 33 (15.2%) patients developed LS in our patient group, all of whom had RT to the ipsilateral neck only. LS patients had a steeper dose gradient between left and right quadrants across all cervical spine levels (repeated-measures ANOVA, p = 0.030). Within the unilateral treatment group, LS patients received a higher mean dose across all seven cervical spinal levels (repeated-measures ANOVA, p = 0.046). Dose gradients in the anterior-posterior direction and mean doses to the cord were not significant between LS and non-LS patients. CONCLUSIONS: Dose gradients along the axial plane of the spinal cord may contribute to LS development; however, a threshold dose within the high dose region of the cord may still be required. This is the first clinical study to suggest that inhomogeneous dose distributions in the cord may be relevant in humans. Further investigation is warranted to determine treatment-planning parameters associated with development of LS.


Assuntos
Neoplasias de Cabeça e Pescoço/radioterapia , Lesões por Radiação/diagnóstico , Radioterapia de Intensidade Modulada , Medula Espinal/efeitos da radiação , Idoso , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/radioterapia , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Radiometria , Dosagem Radioterapêutica , Medula Espinal/diagnóstico por imagem , Tomografia Computadorizada por Raios X
20.
Semin Radiat Oncol ; 25(4): 281-91, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26384276

RESUMO

Radiotherapy is a mainstay of cancer treatment, used in either a curative or palliative manner to treat approximately 50% of patients with cancer. Normal tissue toxicity limits the doses used in standard radiation therapy protocols and impedes improvements in radiotherapy efficacy. Damage to surrounding normal tissues can produce reactions ranging from bothersome symptoms that negatively affect quality of life to severe life-threatening complications. Improved ways of predicting, before treatment, the risk for development of normal tissue toxicity may allow for more personalized treatment and reduce the incidence and severity of late effects. There is increasing recognition that the cause of normal tissue toxicity is multifactorial and includes genetic factors in addition to radiation dose and volume of exposure, underlying comorbidities, age, concomitant chemotherapy or hormonal therapy, and use of other medications. An understanding of the specific genetic risk factors for normal tissue response to radiation has the potential to enhance our ability to predict adverse outcomes at the treatment-planning stage. Therefore, the field of radiogenomics has focused upon the identification of genetic variants associated with normal tissue toxicity resulting from radiotherapy. Innovative analytic methods are being applied to the discovery of risk variants and development of integrative predictive models that build on traditional normal tissue complication probability models by incorporating genetic information. Results from initial studies provide promising evidence that genetic-based risk models could play an important role in the implementation of precision medicine for radiation oncology through enhancing the ability to predict normal tissue reactions and thereby improve cancer treatment.


Assuntos
Neoplasias/radioterapia , Polimorfismo de Nucleotídeo Único/efeitos da radiação , Lesões por Radiação/prevenção & controle , Humanos
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