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1.
Radiat Oncol ; 15(1): 263, 2020 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-33183307

RESUMO

INTRODUCTION: The spine represents the site which is most frequently affected by bone metastases in patients with systemic cancer. Of all local treatment options, combined kyphoplasty and intraoperative radiotherapy (Kypho-IORT) provides both, instantaneous stabilization and immediate pain relief. We here report on the long-term outcomes of the largest cohort treated with Kypho-IORT to date. METHODS: Between 2009 and 2019 a total of 104 patients underwent Kypho-IORT to vertebral tumors in the thoracic, lumbar, or sacral spine with transpedicular kyphoplasty and intraoperative irradiation with a needle-shaped electronic brachytherapy source at our center. Patients were treated either on trial, within the prospective Kypho-IORT studies (NCT01280032 and NCT02773966), or, after completion of the study, off trial but compliant with the study protocol. Follow-up and imaging with computed tomography (CT) or magnetic resonance imaging was scheduled after 3 and 6 months and then bi-annually. RESULTS: A total of 143 vertebrae (89 thoracic spine, 53 lumbar spine, and 1 sacral spine) were treated in 104 patients. The median follow-up was 14.5 months (range 0.4-109). Local progression occurred in 10 patients (10 vertebrae) after a median time of 22.3 months (range 1.5-73) resulting in local control rates of 97.1, 95.9, and 94.2% at 6, 12, and 24 months, respectively. Overall survival was 74.6, 61.7, and 50.3% at 6, 12, and 24 months, respectively. A single serious adverse event was reported. CONCLUSION: In addition to immediate pain reduction and stabilization, Kypho-IORT shows excellent long-term local control with minimal side effects.


Assuntos
Cifoplastia/métodos , Neoplasias da Coluna Vertebral/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Terapia Combinada , Feminino , Humanos , Cifoplastia/efeitos adversos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Dosagem Radioterapêutica , Neoplasias da Coluna Vertebral/mortalidade
2.
Radiother Oncol ; 147: 195-199, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32416280

RESUMO

PURPOSE: The newest generation of the Leksell Gamma Knife (GK) allows frame based as well as frameless treatment. We here report outcomes of a prospective non-randomized study on mask fixation (MF) versus frame fixation (FF) for GK treatment of brain metastases. METHODS: The decision for FF or MF was made on a case-by-case basis. Factors considered were patients' preference, proximity of critical structures, V12 and treatment time. Either stereotactic radiosurgery or fractionated stereotactic radiotherapy in up to 3 fractions was performed. For MF, a PTV margin of 1 mm was added. Follow-up included quarterly MRI scans. The primary outcome was local control. Secondary endpoints were progression-free survival (PFS), overall survival (OS) and the incidence of radionecrosis. RESULTS: A total of 197 lesions (169 FF and 28 MF) were treated in 76 patients (59 FF and 17 MF). 187 lesions were treated with SRS and 10 with FSRT. Median dose was 22 Gy in both groups and median follow-up was 9.3 months. There was a higher local failure rate (HR: 3.69; 95%CI: 1.13-12.0; p = 0.03) with 11 local failures in the FF and none in the MF cohort. No differences were observed between the groups for OS (median: n.r. vs. 16.9 months; HR:1.00; 95%CI: 0.41-2.46; p = 0.999) and PFS (median: 6.9 vs. 8.4 months; HR: 0.92; 95%CI: 0.47-1.79; p = 0.800). Three cases of radionecrosis occurred with FF but none with MF (p = 0.67). CONCLUSIONS: Gamma Knife treatment with MF does not result in worse outcome or increased rates of radionecrosis in this non-randomized study.


Assuntos
Neoplasias Encefálicas , Radiocirurgia , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/cirurgia , Seguimentos , Humanos , Intervalo Livre de Progressão , Estudos Prospectivos , Radiocirurgia/efeitos adversos , Estudos Retrospectivos , Resultado do Tratamento
3.
Strahlenther Onkol ; 196(4): 349-355, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31641788

RESUMO

PURPOSE: To investigate long-term oncological outcome and incidence of chronic side effects in patients with breast cancer and intraoperative radiotherapy given as an upfront boost (IORT boost). METHODS: Retrospective analysis of 400 patients with an IORT boost with low-energy X­rays (20 Gy), subsequent whole-breast irradiation (46-50 Gy), and annual oncological follow-up. Side effects were prospectively evaluated (LENT-SOMA scales) over a period of up to 15 years. Side effects scored ≥grade 2 at least three times during follow-up were judged to be chronic. RESULTS: The median age was 63 years (30-85) and the median follow-up was 78 months (2-180) after IORT boost. In 15 patients a local recurrence occurred, resulting in a local recurrence rate at 5, 10, and 15 years of 2.0%, 6.6%, and 10.1%, respectively. The overall survival rates at 5, 10, and 15 years were 92.1%, 81.8%, and 80.7%, respectively. The most common high-grade side effects were fibrosis (21%) and pain (8.6%). The majority of side effects occurred within the first 3 years. The actuarial rates of chronic fibrosis were 19.1% and 21.1% at 5 and ≥8 years, of chronic pain 8.6% at ≥4 years, of chronic edema of the breast 2.4% at ≥2 years, of chronic lymphedema 0.0% at 5 and 10 years, and of chronic hyperpigmentation 0.5% at ≥2 years. Side effects were similar or less than expected from an external beam boost. CONCLUSION: IORT boost appears to be a highly efficient and safe method for upfront delivery of the tumor bed boost in high-risk breast cancer patients.


Assuntos
Neoplasias da Mama/radioterapia , Neoplasias da Mama/cirurgia , Radioterapia Adjuvante , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/mortalidade , Doença Crônica , Terapia Combinada , Feminino , Seguimentos , Humanos , Período Intraoperatório , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/etiologia , Lesões por Radiação/etiologia , Dosagem Radioterapêutica , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do Tratamento
4.
Strahlenther Onkol ; 196(3): 205-212, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31740981

RESUMO

PURPOSE AND OBJECTIVE: Randomized trials indicate that electronic or app-based assessment of patient-reported outcomes may improve outcomes in cancer patients. To analyze if an app-based follow-up would be accepted by elderly cancer patients, we conducted a single-center prospective feasibility study (NCT03196050). MATERIALS AND METHODS: Cancer patients (≥60 years) without concurrent uncontrolled severe medical conditions and a Karnofsky performance status (KPS) ≥70 were eligible if they were able to use the smartphone app. The primary endpoint was compliance over 1 year, calculated as patient-specific and study date-specific response rate to questions sent as push notifications; in this interim analysis, we report on 4­month data. Secondary outcomes included a comparison of a subjective health status item (SPHS) with the physician-rated KPS. RESULTS: Out of 225 patients screened, 54 patients agreed to participate and 29 activated the app and participated in the study. The mean age was 66 years (61-78). The individual compliance rate averaged at 58.3% (standard deviation SD = 35%). Daily compliance was 53.3% on average (SD = 10.8%) and declined over time. The average percentage of patients who sent answers at least weekly was 75.0% (SD = 14.8%) and declined from 100% in week 1 to 53.8% in week 17 post-enrollment. Secondary outcomes indicated that questionnaires such as the EORTC-QLQ-C30 are accepted via app and that there is a significant moderate correlation between the SPHS and KPS scores (r = 0.566; p < 0.001). CONCLUSION: Our data indicate that an app-based follow-up incorporating EORTC questionnaires might be possible in highly selected elderly cancer patients with modest compliance rates. Further trials should aim at an increased participation rate.


Assuntos
Aplicativos Móveis , Neoplasias/terapia , Smartphone , Telemedicina , Idoso , Estudos de Viabilidade , Feminino , Nível de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Cooperação do Paciente , Pacientes , Estudos Prospectivos , Qualidade de Vida , Inquéritos e Questionários , Telemedicina/instrumentação
5.
Oncology ; 98(6): 379-385, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-30517946

RESUMO

There is accumulating evidence from randomized trials suggesting that digital patient-centered care allows a more reliable detection of tumour-related symptoms and adverse events - with a direct impact on overall survival. Consequently, a variety of unsynchronized approaches were kicked off to (electronically) measure patient-reported outcomes (PROs). Despite increasing evidence that PRO data are highly relevant for patient care, the data generated in these initial projects lack standardized processing pathways in order to impact clinical routine; therefore, potential future routine PRO assessments require adequate analysis, storage and processing to allow a robust, reproducible and reliable incorporation into routine clinical decision-making. Here, we discuss relevant challenges of digital follow-up that need to be tackled to render PRO data as relevant to physicians as laboratory or biomarker data.


Assuntos
Oncologia/métodos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Assistência Centrada no Paciente/métodos , Seguimentos , Humanos , Medidas de Resultados Relatados pelo Paciente
6.
BMC Cancer ; 19(1): 430, 2019 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-31072314

RESUMO

BACKGROUND: The spine is the most frequent location of bone metastases. Local treatment aims at palliation of pain and, given the increased likelihood of long-term cancer survival, at local control. Kyphoplasty and intraoperative radiotherapy (Kypho-IORT) provided instantaneous pain relief in 70% of patients at the first day after the intervention and resulted in local control rates of > 93% at 1 year in a recently conducted phase I/II trial. To assess its clinical value, we designed a phase III trial which tests Kypho-IORT against the most widespread standard-of-care, external beam radiotherapy (EBRT), in patients with painful vertebral metastases. METHODS: This phase III study includes patients ≥50 years of age with up to 4 vertebral metastases and a pain score of at least 3/10 points on the visual/numeric analogy scale (VAS). Patients randomized into the experimental arm (A) will undergo Kypho-IORT (Kyphoplasty plus IORT with 8 Gy prescribed to 13 mm depth). Patients randomized into the control arm (B) will receive EBRT with either 30 Gy in 10 fractions or 8 Gy as a single dose. The primary end point is pain reduction defined as at least - 3 points on the VAS compared to baseline at day 1. Assuming that 40% of patients in the Kypho-IORT arm and 5% of patients in the control arm will achieve this reduction and 20% will drop out, a total of 54 patients will have to be included to reach a power of 0.817 with a two-sided alpha of 0.05. Secondary endpoints are evaluation of the percentage of patients with a pain reduction of at least 3 points at 2 and 6 weeks, local tumor control, frequency of re-intervention, secondary fractures/sintering, complication rates, skin toxicity/wound healing, progression-free survival (PFS), overall survival (OS) and quality of life. DISCUSSION: This trial will generate level 1 evidence on the clinical value of a one-stop procedure which may provide instantaneous pain relief, long-term control and shortened intervals to further adjuvant (systemic) therapies in patients with spinal metastases. TRIAL REGISTRATION: Registered with ClinicalTrials.gov, number: NCT02773966 (Registration date: 05/16/2016).


Assuntos
Dor do Câncer/terapia , Cuidados Intraoperatórios/métodos , Cifoplastia/métodos , Manejo da Dor/métodos , Neoplasias da Coluna Vertebral/terapia , Dor do Câncer/diagnóstico , Dor do Câncer/etiologia , Ensaios Clínicos Fase III como Assunto , Terapia Combinada/métodos , Fracionamento da Dose de Radiação , Humanos , Pessoa de Meia-Idade , Medição da Dor , Intervalo Livre de Progressão , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Neoplasias da Coluna Vertebral/complicações , Neoplasias da Coluna Vertebral/mortalidade , Neoplasias da Coluna Vertebral/secundário , Coluna Vertebral/efeitos da radiação , Coluna Vertebral/cirurgia
7.
Strahlenther Onkol ; 195(7): 640-647, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30796496

RESUMO

PURPOSE: Partial breast irradiation using intraoperative radiotherapy (IORT) after breast-conserving surgery could be sufficient for a selected group of breast cancer patients. We report the results of a cohort of patients from a single center treated as part of the randomized phase-3 TARGIT-A trial. METHODS: Patients (≥50 years) with cT1 cN0 cM0 and invasive ductal histology on biopsy were randomized between IORT with 20 Gy (arm-A) or postoperative whole-breast RT (WBRT) up to 56 Gy in 2 Gy fractions (arm-B). Postoperatively, patients in arm-A with multifocality, lymphovascular invasion, nodal invasion, extensive intraductal component, invasive lobular carcinoma, or resection margins <1 cm received additional postoperative WBRT. RESULTS: Between 2002 and 2012, 184 patients were randomized, of whom 90 in arm-A and 90 in arm-B were evaluated. Median follow-up was 8.5 years. The 5­year overall survival was 94.4% in arm-A and 93.3% in arm-B (p = 0.73). Two local recurrences were observed: one at 70.3 months in an arm-A patient who received IORT + WBRT and another at 4.5 months in an arm-B patient who refused all forms of adjuvant treatment, thus resulting in a 5-year local recurrence of 0% in arm-A and 1.1% in arm-B. The 5­year in-breast recurrence (outside of the index quadrant) was 0% in arm-A and 1.2% in arm-B. Salvage mastectomy was performed successfully in all patients with relapse. CONCLUSION: Long-term follow-up of this single-center cohort consolidates the earlier reports of low local recurrence rates after single-dose IORT. Our results are in line with non-inferiority of risk-adapted IORT for selected patients with early breast cancer.


Assuntos
Neoplasias da Mama/radioterapia , Neoplasias da Mama/cirurgia , Carcinoma Ductal de Mama/radioterapia , Carcinoma Ductal de Mama/cirurgia , Mastectomia Segmentar , Terapia Neoadjuvante , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/mortalidade , Carcinoma Ductal de Mama/patologia , Estudos de Coortes , Terapia Combinada , Seguimentos , Humanos , Período Intraoperatório , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Taxa de Sobrevida
8.
Neurosurgery ; 84(1): 41-49, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29528443

RESUMO

BACKGROUND: The median time to recurrence of glioblastoma (GB) following multimodal treatment is ∼7 mo. Nearly all cancers recur locally, suggesting that augmenting local treatments may improve outcomes. OBJECTIVE: To investigate whether intraoperative radiotherapy (IORT) to the resection cavity is safe and effective. METHODS: INTRAGO was a phase I/II trial to evaluate the safety and tolerability of IORT with 20 to 40 Gy of low-energy photons in addition to standard radiochemotherapy (ClinicalTrials.gov ID, NCT02685605). The primary endpoint was safety as per occurrence of dose-limiting toxicities. Secondary endpoints were progression-free survival (PFS) and overall survival (OS). We also performed an exploratory analysis of the local PFS (L-PFS), defined as recurrence within 1 cm of the treated margin. RESULTS: Fifteen patients were treated at 3 dose levels. Of these, 13 underwent incomplete resection, 6 had unresected satellites, and 3 did not receive per-protocol treatment (PPT). The MGMT promoter was unmethylated in 10 patients. The median follow-up was 13.8 mo. The majority of grade 3 to 5 adverse events were deemed unrelated to IORT. Five cases of radionecrosis were observed, 2 were classified as grade 3 events. Other grade 3 events judged related to radiotherapy (external-beam radiotherapy and/or IORT) were wound dehiscence (n = 1), CSF leakage (n = 1), cyst formation (n = 1). No IORT-related deaths occurred. The median PFS was 11.2 mo (95% confidence interval [CI]: 5.4-17.0) for all patients and 11.3 mo (95% CI: 10.9-11.6) for those receiving PPT. The median L-PFS was 14.3 mo (95% CI: 8.4-20.2) for all patients and 17.8 mo (95% CI: 9.7-25.9) for those receiving PPT. The median OS was 16.2 mo (95% CI: 11.1-21.4) for all patients and 17.8 mo (95% CI: 13.9-21.7) for those receiving PPT. CONCLUSION: These data suggest that IORT is associated with manageable toxicity. Considering the limitations of a 15-patient phase I/II trial, further studies aimed at assessing an outcome benefit are warranted.


Assuntos
Neoplasias Encefálicas/radioterapia , Glioblastoma/radioterapia , Cuidados Intraoperatórios , Radioterapia/métodos , Idoso , Quimiorradioterapia , Terapia Combinada , Relação Dose-Resposta à Radiação , Determinação de Ponto Final , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Radioterapia/efeitos adversos , Resultado do Tratamento
9.
Neurosurgery ; 84(5): 1133-1137, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29688510

RESUMO

BACKGROUND: Glioblastoma (GBM) is the most common malignant brain tumor in adult patients. Tumor recurrence commonly occurs around the resection cavity, especially after subtotal resection (STR). Consequently, the extent of resection correlates with overall survival (OS), suggesting that depletion of postoperative tumor remnants will improve outcome. OBJECTIVE: To assess safety and efficacy of adding stereotactic radiosurgery (SRS) to the standard treatment of GBM in patients with postoperative residual tumor. METHODS: Gamma-GBM is a single center, open-label, prospective, single arm, phase II study that includes patients with newly diagnosed GBM (intraoperative via frozen sections) who underwent STR (residual tumor will be identified by native and contrast enhanced T1-weighted magnetic resonance imaging scans). All patients will receive SRS with 15 Gy (prescribed to the 50% isodose enclosing all areas of residual tumor) early (within 24-72 h) after surgery. Thereafter, all patients undergo standard-of-care therapy for GBM (radiochemotherapy with 60 Gy external beam radiotherapy [EBRT] plus concomitant temozolomide and 6 cycles of adjuvant temozolomide chemotherapy). The primary outcome is median progression-free survival, secondary outcomes are median OS, occurrence of radiation induced acute (<3 wk), early delayed (<3 mo), and late (>3 mo post-SRS) neurotoxicity and incidence of symptomatic radionecrosis. EXPECTED OUTCOMES: We expect to detect efficacy and safety signals by the immediate application of SRS to standard-of-care therapy in newly diagnosed GBM. DISCUSSION: Early postoperative SRS to areas of residual tumor could bridge the therapeutic gap between surgery and adjuvant therapies.


Assuntos
Neoplasias Encefálicas/cirurgia , Glioblastoma/cirurgia , Neoplasia Residual/cirurgia , Radiocirurgia/métodos , Adulto , Idoso , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Quimiorradioterapia Adjuvante/métodos , Feminino , Glioblastoma/mortalidade , Glioblastoma/patologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Neoplasia Residual/mortalidade , Intervalo Livre de Progressão , Estudos Prospectivos , Lesões por Radiação/epidemiologia , Lesões por Radiação/etiologia , Radiocirurgia/efeitos adversos , Radiocirurgia/mortalidade , Projetos de Pesquisa
10.
Health Qual Life Outcomes ; 16(1): 21, 2018 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-29357874

RESUMO

BACKGROUND: Patient-reported health-related quality of life (HRQOL) differs between treatment options for prostate carcinoma. Long-term HRQOL data in brachytherapy series are scarce. Therefore, we analyzed prostate-specific and general HRQOL in patients treated with brachytherapy for prostate carcinoma after long-term follow-up. METHODS: Two hundred ninety-six patients with prostate carcinoma were treated with brachytherapy (01/1998-11/2003). General and prostate-specific HRQOL were measured using EORTC-QLQ-C30 and EORTC-QLQ-PR25, respectively. Patients were asked to complete the questionnaires after a median follow-up of 141 (119-181) months. QLQ-C30 results were compared to the German reference population. QLQ-PR25 results were compared to an earlier follow-up after a median of 51 months (no published QLQ-PR25 reference population for comparison). Additionally, a literature review on HRQOL data in brachytherapy series was performed. RESULTS: One hundred six (35.8%) patients were lost to follow-up, 70 (23.6%) had died. 120 (40.5%) patients were contacted. 80 questionnaires were returned (27% of the original cohort; 91% of alive patients were ≥70 years). Sexual activity declined over time (mean scores: 40.5 vs. 45.5; p = 0.006), hormonal treatment-related symptoms, problems associated with incontinence aids, and burden of obstructive urinary symptoms did not differ significantly compared to the 51-month follow-up. General HRQOL was numerically better in our cohort as compared to the German reference population (> 16% relative difference for both age strata; < 70 and ≥70 years). CONCLUSIONS: Our results indicate that symptom-burden after long-term follow-up and associated prostate-specific HRQOL remains relatively stable from 51 to 141 months. General HRQOL in surviving patients was numerically better compared to the reference population.


Assuntos
Braquiterapia , Neoplasias da Próstata/radioterapia , Qualidade de Vida , Idoso , Idoso de 80 Anos ou mais , Braquiterapia/efeitos adversos , Braquiterapia/métodos , Disfunção Erétil/psicologia , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Medidas de Resultados Relatados pelo Paciente , Dosagem Radioterapêutica , Estatísticas não Paramétricas , Inquéritos e Questionários , Fatores de Tempo , Incontinência Urinária/psicologia
11.
Spine J ; 18(5): 776-781, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-28962909

RESUMO

BACKGROUND CONTEXT: Spinal metastases occur in 30%-50% of patients with systemic cancer. The primary goals of palliation are pain control and prevention of local recurrence. PURPOSE: This study aimed to test the safety and efficacy of a combined modality approach consisting of kyphoplasty and intraoperative radiotherapy (Kypho-IORT). STUDY DESIGN/SETTING: Kyphoplasty and intraoperative radiotherapy was a prospective, single-center phase I/II trial. Patients were enrolled in a classical 3+3 scheme within the initial phase I, where Kypho-IORT was applied using a needle-shaped 50 kV X-ray source at three radiation dose levels (8 Gy in 8-mm, 8 Gy in 11-mm, and 8 Gy in 13-mm depth). Thereafter, cohort expansion was performed as phase II of the trial. The trial is registered with clinicaltrials.gov, number NCT01280032. PATIENT SAMPLE: Patients aged 50 years and older with a Karnofsky Performance Status of at least 60% and with one to three painful vertebral metastases confined to the vertebral body were eligible to participate. OUTCOME MEASURES: The primary end point was safety as per the occurrence of dose-limiting toxicities. The secondary end points were pain reduction, local progression-free survival (L-PFS), and overall survival (OS). METHODS: Pain was measured using the visual analog scale (VAS) and local control was assessed in serial computed tomography or magnetic resonance imaging scans. RESULTS: None of the nine patients enrolled in the phase I showed dose-limiting toxicities at any level and thus, 52 patients were subsequently enrolled into a phase II, where Kypho-IORT was performed at various dose levels. The median pain score significantly dropped from 5 preoperatively to 2 at the first postoperative day (p<.001). Of 43 patients who reported a pre-interventional pain level of 3 or more, 30 (69.8%) reported a reduction of ≥3 points on the first postoperative day. A persistent pain reduction beyond the first postoperative day of ≥3 points was seen in 34 (79.1%) patients. The 3, 6, and 12 month L-PFS was excellent with 97.5%, 93.8%, and 93.8%. The 3, 6, and 12 months OS was 76.9%, 64.0%, and 48.4%. CONCLUSION: Kyphoplasty and intraoperative radiotherapy is safe and immediately provided sustained pain relief with excellent local control rates in patients with painful vertebral metastases.


Assuntos
Cifoplastia/métodos , Recidiva Local de Neoplasia/prevenção & controle , Complicações Pós-Operatórias/epidemiologia , Radioterapia/métodos , Neoplasias da Coluna Vertebral/cirurgia , Idoso , Terapia Combinada , Feminino , Humanos , Cifoplastia/efeitos adversos , Masculino , Pessoa de Meia-Idade , Manejo da Dor/efeitos adversos , Manejo da Dor/métodos , Radioterapia/efeitos adversos , Neoplasias da Coluna Vertebral/radioterapia , Neoplasias da Coluna Vertebral/secundário
12.
Oncotarget ; 7(29): 45500-45512, 2016 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-27275537

RESUMO

Patients with actively replicating human immunodeficiency virus (HIV) exhibit adverse reactions even to low irradiation doses. High levels of the virus-encoded viral protein R (Vpr) are believed to be one of the major underlying causes for increased radiosensitivity. As Vpr efficiently crosses the blood-brain barrier and accumulates in astrocytes, we examined its efficacy as a drug for treatment of glioblastoma multiforme (GBM).In vitro, four glioblastoma-derived cell lines with and without methylguanine-DNA methyltransferase (MGMT) overexpression (U251, U87, U251-MGMT, U87-MGMT) were exposed to Vpr, temozolomide (TMZ), conventional photon irradiation (2 to 6 Gy) or to combinations thereof. Vpr showed high rates of acute toxicities with median effective doses of 4.0±1.1 µM and 15.7±7.5 µM for U251 and U87 cells, respectively. Caspase assays revealed Vpr-induced apoptosis in U251, but not in U87 cells. Vpr also efficiently inhibited clonogenic survival in both U251 and U87 cells and acted additively with irradiation. In contrast to TMZ, Vpr acted independently of MGMT expression.Dose escalation in mice (n=12) was feasible and resulted in no evident renal or liver toxicity. Both, irradiation with 3x5 Gy (n=8) and treatment with Vpr (n=5) delayed intracerebral tumor growth and prolonged overall survival compared to untreated animals (n=5; p3x5 Gy<0.001 and pVpr=0.04; log-rank test).Our data show that the HIV-encoded peptide Vpr exhibits all properties of an effective chemotherapeutic drug and may be a useful agent in the treatment of GBM.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias Encefálicas/patologia , Glioma/patologia , Produtos do Gene vpr do Vírus da Imunodeficiência Humana/farmacologia , Animais , Linhagem Celular Tumoral , Humanos , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Int J Radiat Oncol Biol Phys ; 93(4): 819-27, 2015 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-26530750

RESUMO

PURPOSE: Human papillomavirus (HPV) DNA and p16 status have both been reported as prognostic factors in anal cancer, but the prognostic relevance of combined detection and particularly HPV-/p16+ and HPV+/p16- signatures is unknown. We evaluated combined HPV DNA and p16 status as a prognostic factor of treatment response in anal cancer. METHODS: 106 patients treated with radiochemotherapy (RCT+5-FU/MMC) with available paraffin-embedded tumor tissue specimens were evaluated regarding local control (LC) and overall survival (OS) at 5 years. In addition to HPV DNA/p16 status, the influence of age, gender, previous surgery, initial recurrence, T stage, N status, and tumor localization was analyzed. RESULTS: 63 patients were HPV+/p16+, 9 were HPV+/p16-, 11 were HPV-/p16+, and 23 were HPV-/p16-. In univariate analysis, LC was significantly better in patients with T1/2 stage, female gender, and HPV/p16 status. HPV+/p16+ was associated with significantly better LC (88.1%; 95% confidence interval [CI]: 78.89-97.31) compared with HPV-/p16+ (63.6%; 95% CI: 35.18-92.02; P=.021) and especially HPV-/p16- (55.8%; 95% CI: 33.46-78.14; P=.002) but not with HPV+/p16- (77.8%; 95% CI: 50.56-105.04; P=.270). OS was influenced by T stage and LC. HPV+/p16+ patients showed a trend toward better OS compared with HPV-/p16- patients (HPV+/p16+: 81.1%; 95% CI: 70.12-92.08 vs HPV-/p16-: 68.8%; 95%CI: 47.44-90.16; P=.138). On multivariate analysis, T3/4 stage and HPV/p16 status (HPV-/p16+, HPV-/p16- vs HPV+/p16+) predicted poorer LC (T3/4: 50.3% vs T1/2: 86.6%, hazard ratio [HR] 0.22; 95% CI: 0.09-0.53; P<.001; HPV+/p16+ vs HPV-/p16+: HR 4.73; 95% CI: 1.33-16.82; P=.016, and HPV+/p16+ vs HPV-/p16-: HR 6.40; 95% CI: 2.23-18.35; P<.001), whereas local relapse dramatically influenced OS. CONCLUSION: Our data suggest that HPV/p16 signature determines prognosis. HPV+/p16+ patients had the best prognosis, and HPV-/p16+ and HPV-/p16- patients showed the worst outcome and therefore require therapy optimization, particularly given that LC is the most important factor for OS.


Assuntos
Neoplasias do Ânus/metabolismo , Neoplasias do Ânus/virologia , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/virologia , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , DNA Viral/análise , Infecções por Papillomavirus/complicações , Adulto , Fatores Etários , Idoso , Análise de Variância , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Ânus/mortalidade , Neoplasias do Ânus/patologia , Neoplasias do Ânus/terapia , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/terapia , Quimiorradioterapia/métodos , Feminino , Fluoruracila/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Mitomicina/administração & dosagem , Estadiamento de Neoplasias , Papillomaviridae/genética , Infecções por Papillomavirus/mortalidade , Prognóstico , Estudos Retrospectivos , Fatores Sexuais , Análise de Sobrevida , Fatores de Tempo
14.
Int J Radiat Oncol Biol Phys ; 93(4): 836-44, 2015 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-26530752

RESUMO

PURPOSE: Breast intensity modulated radiation therapy (IMRT) reduces high-dose heart volumes but increases low-dose volumes. We prospectively assessed heart changes after 3D conformal RT (3DCRT) and IMRT for left-sided breast cancer. Heart dose was analyzed individually, 3DCRT patients were moderately exposed, and IMRT was performed only in patients with unacceptably high heart doses upon 3DCRT planning. METHODS AND MATERIALS: In 49 patients (38 patients received 3DCRT; 11 patients received IMRT; and 20 patients received neoadjuvant or adjuvant chemotherapy) magnetic resonance imaging (MRI) and echocardiography were performed before and at 6, 12, and 24 months after treatment. RESULTS: Mean heart dose for IMRT was 12.9 ± 3.9 Gy versus 4.5 ± 2.4 Gy for 3DCRT. Heart volumes receiving >40 Gy were 2.6% (3DCRT) versus 1.3% (IMRT); doses were >50 Gy only with 3DCRT. Temporary ejection fraction (EF) decrease was observed on MRI after 6 months (63%-59%, P=.005) resolving at 24 months. Only 3 patients had pronounced largely transient changes of EF and left ventricular enddiastolic diameter (LVEDD). Mitral (M) and tricuspid (T) annular plane systolic excursion (MAPSE and TAPSE) were reduced over the whole cohort (still within normal range). After 24 months left ventricular remodeling index decreased in patients receiving chemotherapy (0.80 vs 0.70, P=.028). Neither wall motion abnormalities nor late enhancements were found. On echocardiography, in addition to EF findings that were similar to those on MRI, global strain was unchanged over the whole cohort at 24 months after a transient decrease at 6 and 12 months. Longitudinal strain decreased in the whole cohort after 24 months in some segments, whereas it increased in others. CONCLUSIONS: Until 24 months after risk-adapted modern multimodal adjuvant therapy, only subclinical cardiac changes were observed in both 3DCRT patients with inclusion of small to moderate amounts of heart volume in RT tangents and in the patients treated with IMRT and reduced high-dose heart exposure.


Assuntos
Coração/efeitos da radiação , Radioterapia Conformacional/métodos , Neoplasias Unilaterais da Mama/radioterapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Cardiotoxicidade/epidemiologia , Cardiotoxicidade/etiologia , Quimioterapia Adjuvante , Ecocardiografia , Feminino , Coração/efeitos dos fármacos , Coração/fisiologia , Humanos , Imageamento por Ressonância Magnética , Mastectomia , Pessoa de Meia-Idade , Órgãos em Risco/efeitos da radiação , Estudos Prospectivos , Doses de Radiação , Dosagem Radioterapêutica , Radioterapia Adjuvante , Radioterapia de Intensidade Modulada/métodos , Volume Sistólico/efeitos dos fármacos , Volume Sistólico/fisiologia , Volume Sistólico/efeitos da radiação , Neoplasias Unilaterais da Mama/tratamento farmacológico , Função Ventricular Esquerda/efeitos dos fármacos , Função Ventricular Esquerda/fisiologia , Função Ventricular Esquerda/efeitos da radiação
15.
Breast Care (Basel) ; 10(4): 247-52, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26600760

RESUMO

Accelerated partial breast irradiation (APBI) has been under clinical investigation for more than 15 years. There are several technical approaches that are clinically established, e.g. brachytherapy, intraoperative radiotherapy (IORT), or external-beam radiotherapy. The understanding of the underlying biology, optimal technical procedures, patient selection criteria, and imaging changes during follow-up has increased enormously. After completion of several phase III trials using brachytherapy or IORT, APBI is currently increasingly used either in phase IV studies, registries, or in selected patients outside of clinical studies. Consensus statements about suitable patients are available from several international and national societies like ASTRO, ESTRO, and DEGRO. One may expect that 15-25% of patients undergoing breast-conserving surgery may qualify for APBI, i.e. patients with small invasive ductal breast cancer without clinical lymph node involvement.

16.
J Neurooncol ; 124(2): 265-73, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26045360

RESUMO

Chemotherapy is often omitted in elderly patients with glioblastoma multiforme due to a fear of side effects. We applied metronomic chemotherapy with low-dose temozolomide and celecoxib (LD-TEM/CEL) during and after external beam radiotherapy (EBRT) and here report on how this regimen compares to standard temozolomide radiochemotherapy (SD-TEM) in elderly patients. We retrospectively analyzed records of 146 patients aged 65 years and older that underwent EBRT. Factors of interest were age, performance status, comorbidities, MGMT status, therapy (resection/biopsy, radiotherapy/dose, chemotherapy/regimen/dose), progression-free (PFS) and overall survival (OS) status. Irrespective of the regimen, addition of chemotherapy more than doubled median survival rates (EBRT only: 4.2 months; EBRT + LD-TEM/CEL: 8.5 months; EBRT + SD-TEM: 10.8 months; p ≤ 0.008). Although patients receiving metronomic LD-TEM/CEL were significantly older (62 % were ≥75 years vs. 22 %; p < 0.001), had significantly lower performance scores (50 % had a KPS <70 vs. 28 %; p = 0.049) and were significantly more comorbid (73 % had ≥4 comorbidities vs. 37 %; p = 0.002) than patients of the SD-TEM group, there were no significant differences in PFS and OS. Independent of other factors, omission of chemotherapy significantly impairs progression-free and overall survival. With all the limitations of a retrospective analysis, our data suggest that metronomic chemotherapy with LD-TEM/CEL may be equieffective and eventually better tolerated than SD-TEM. It may be offered to elderly patients that are not eligible for standard chemotherapy.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias Encefálicas/terapia , Celecoxib/administração & dosagem , Dacarbazina/análogos & derivados , Glioblastoma/terapia , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Neoplasias Encefálicas/epidemiologia , Neoplasias Encefálicas/patologia , Celecoxib/efeitos adversos , Quimiorradioterapia , Comorbidade , Inibidores de Ciclo-Oxigenase 2/administração & dosagem , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Dacarbazina/administração & dosagem , Dacarbazina/efeitos adversos , Esquema de Medicação , Feminino , Seguimentos , Glioblastoma/epidemiologia , Glioblastoma/patologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Gradação de Tumores , Estudos Retrospectivos , Análise de Sobrevida , Temozolomida , Resultado do Tratamento
17.
Radiat Oncol ; 10: 30, 2015 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-25636703

RESUMO

BACKGROUND: Current therapeutic standard for locally advanced rectal cancer is the neoadjuvant radiochemotherapy with total mesorectal excision. Diarrhoea is the main acute side effect, induced by the dose to the small-bowel, frequently leading to a treatment modification. Aim of this study was to analyse the differences between the irradiated small-bowel volumes and the occurrence of acute diarrhea during combined radiochemotherapy for rectal cancer. METHODS: 45 patients treated with a neoadjuvant radiochemotherapy (three-field box 50.4 Gy; Cetuximab, Capecitabine, Irinotecan) for locally advanced rectal cancer within a prospective phase I/II study were evaluated. Based on the dose-volume histograms, the small-bowel volumes receiving doses of 5, 10 … 45 Gy (V5, V10 …V45) were calculated and compared with the prospectively documented small- bowel toxicities. RESULTS: There was a statistically significant difference between irradiated small-bowel volumes and the severity of therapy related diarrhoea. The strongest validity concerning the risk of developing a grade 2-3 diarrhoea was seen at a dose level of 5 Gy (V 5) with a small-bowel volume of 291.94 cc. Patients with V 5 > 291.94 cc had significantly more often grade 2-3 diarrhoea, than patients with V5 below this cut-off value (82% vs. 29%; p < 0.0001). CONCLUSIONS: In the inverse treatment planning of rectal caner patients the small-bowel volume receiving 5 Gy should be limited to about 300 cc.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimiorradioterapia/efeitos adversos , Diarreia/etiologia , Intestino Delgado/patologia , Terapia Neoadjuvante/efeitos adversos , Lesões por Radiação/etiologia , Neoplasias Retais/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Capecitabina/administração & dosagem , Cetuximab/administração & dosagem , Diarreia/diagnóstico , Feminino , Seguimentos , Humanos , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/efeitos da radiação , Irinotecano , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/terapia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos Prospectivos , Lesões por Radiação/diagnóstico , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador/métodos , Radioterapia de Intensidade Modulada/métodos , Neoplasias Retais/patologia
18.
BMC Cancer ; 14: 992, 2014 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-25535398

RESUMO

BACKGROUND: Glioblastoma multiforme (GBM) is the most frequent primary malignant brain tumor in adults. Despite multimodal therapies, almost all GBM recur within a narrow margin around the initial resected lesion. Thus, novel therapeutic intensification strategies must target both, the population of dispersed tumor cells around the cavity and the postoperative microenvironment. Intraoperative radiotherapy (IORT) is a pragmatic and effective approach to sterilize the margins from persistent tumor cells, abrogate post-injury proliferative stimuli and to bridge the therapeutic gap between surgery and radiochemotherapy. Therefore, we have set up INTRAGO, a phase I/II dose-escalation study to evaluate the safety and tolerability of IORT added to standard therapy in newly diagnosed GBM. In contrast to previous approaches, the study involves the application of isotropic low-energy (kV) x-rays delivered by spherical applicators, providing optimal irradiation properties to the resection cavity. METHODS/DESIGN: INTRAGO includes patients aged 50 years or older with a Karnofsky performance status of at least 50% and a histologically confirmed (frozen sections) supratentorial GBM. Safety and tolerability (i.e., the maximum tolerated dose, MTD) will be assessed using a classical 3 + 3 dose-escalation design. Dose-limiting toxicities (DLT) are wound healing deficits or infections requiring surgical intervention, IORT-related cerebral bleeding or ischemia, symptomatic brain necrosis requiring surgical intervention and early termination of external beam radiotherapy (before the envisaged dose of 60 Gy) due to radiotoxicity. Secondary end points are progression-free and overall survival. TRIAL REGISTRATION: The study is registered with clinicaltrials.gov, number: NCT02104882 (Registration Date: 03/26/2014).


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/cirurgia , Protocolos Clínicos , Glioblastoma/diagnóstico por imagem , Glioblastoma/cirurgia , Cuidados Intraoperatórios , Terapia Combinada , Humanos , Radiografia , Dosagem Radioterapêutica
19.
Radiat Oncol ; 9: 154, 2014 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-25015740

RESUMO

BACKGROUND: Since the results from the randomized TARGIT A trial were published, intraoperative radiotherapy (IORT) is used more often. IORT can be provided as accelerated partial breast irradiation (APBI) or as a boost. The definition of suitable patients for IORT as APBI differs between different national societies (e.g. ESTRO and ASTRO) and different inclusion criteria of trials and so does the eligibility of patients. This analysis identifies eligible patients for IORT according to available consensus statements and inclusion criteria of the ongoing TARGIT trials. METHODS: Between 01/03 - 12/09, 1505 breast cancer cases were treated at the breast cancer center at the University Medical Center Mannheim. Complete data sets for age, stage (T, N, and M), histology and hormone receptor status were available in 1108 cases. Parameters to identify eligible patients are as follows: ESTRO: >50 years, invasive ductal carcinoma/other favorable histology (IDC), T1-2 (≤3 cm), N0, any hormone receptor status, M0; ASTRO: ≥60 years, IDC, T1, N0, positive estrogen hormone receptor status, M0; TARGIT E "elderly", risk adapted radiotherapy with IORT followed by external beam radiotherapy in case of risk factors in final histopathology, phase II: ≥70 years, IDC, T1, N0, any hormone receptor status, M0; TARGIT C "consolidation", risk adapted radiotherapy, phase IV: ≥50 years, IDC, T1, N0, positive hormone receptor status, M0; TARGIT BQR "boost quality registry": every age, every histology, T1-2 (max. 3.5 cm), any hormone receptor status, N0/+, M0/+. RESULTS: Out of the 1108 cases, 379 cases (34.2%) were suitable for IORT as APBI regarding the ESTRO and 175 (15.8%) regarding the ASTRO consensus statements. 82 (7.4%) patients were eligible for the TARGIT E trial, 258 (23.3%) for the TARGIT C trial and 671 (60.6%) for the TARGIT BQR registry. According to the consensus statements of ASTRO (45.1%) and ESTRO (41.4%) about half of the eligible patients were treated with IORT as APBI. From the eligible patients fulfilling the criteria for IORT boost (35%) about one third was eventually treated. CONCLUSIONS: Patient selection for IORT should be restrictive. For IORT as APBI the TARGIT trials are even more restrictive including patients than the ESTRO and ASTRO consensus statements.


Assuntos
Neoplasias da Mama/radioterapia , Carcinoma Ductal de Mama/radioterapia , Cuidados Intraoperatórios , Seleção de Pacientes , Idoso , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Carcinoma Ductal de Mama/patologia , Carcinoma Ductal de Mama/cirurgia , Estudos de Coortes , Terapia Combinada , Feminino , Seguimentos , Humanos , Mastectomia Segmentar , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Dosagem Radioterapêutica , Taxa de Sobrevida
20.
Radiat Oncol ; 8: 276, 2013 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-24279376

RESUMO

PURPOSE: Evaluation of dose escalated salvage radiotherapy (SRT) in patients after radical prostatectomy (RP) who had never received antihormonal therapy. To investigate prognostic factors of the outcome of SRT and to analyze which patient subsets benefit most from dose escalation. MATERIALS AND METHODS: Between 2002 and 2008, 76 patients were treated in three different dose-groups: an earlier cohort treated with 66 Gy irrespective of pre-RT-characteristics and two later cohorts treated with 70 Gy or 75 Gy depending on pre-RT-characteristics. Biochemical-relapse-free-survival (bRFS), clinical-relapse-free-survival (cRFS) and late toxicity were evaluated. RESULTS: Four-year bRFS and cRFS were 62.5% and 85%. Gleason score <8, positive surgical resection margin (PSRM) and low PSA (≤0.5 ng/ml) before SRT resulted in higher bRFS. Analysis of the whole group showed no clear dose-outcome relationship. Patients with PSRM, however, had improved bRFS when escalating >66 Gy. While > 70 Gy did not improve the overall results, 4-year bRFS for patients with manifest local recurrence in the high-dose group was still comparable to those without manifest local recurrences. No grade 4 and minimal grade 3 gastrointestinal and urinary toxicity were observed. CONCLUSIONS: Dose-escalated SRT achieves high biochemical control. The data strongly support the application of at least 70 Gy rather than 66 Gy. They do not prove positive effects of doses >70 Gy but do not disprove them as these doses were only applied to an unfavorable patients selection.


Assuntos
Prostatectomia/métodos , Neoplasias da Próstata/radioterapia , Neoplasias da Próstata/cirurgia , Radioterapia/métodos , Idoso , Estudos de Coortes , Intervalo Livre de Doença , Relação Dose-Resposta à Radiação , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/radioterapia , Prognóstico , Dosagem Radioterapêutica , Recidiva , Terapia de Salvação/métodos , Resultado do Tratamento
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