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1.
Artigo em Inglês | MEDLINE | ID: mdl-32607638

RESUMO

PURPOSE: To explore the optimal type of breast reconstruction and the time interval to postmastectomy radiotherapy (PMRT) associated with lower complications in breast cancer patients receiving neoadjuvant chemotherapy. METHODS: We reviewed the medical records of 300 patients who received neoadjuvant chemotherapy, mastectomy with breast reconstruction and PMRT at our institution from 2000 to 2017. Reconstruction types included autologous flaps (AR), single-stage-direct-to-implant and two-stages expander/implant (TE/I). The primary endpoint was the rate of reconstruction complications including infection, skin and fat necrosis. Subgroup analysis compared rates of capsular contracture, implant rupture, implant exposure and overall implant failure in single-stage-direct-to-implant to TE/I. The secondary endpoint was identifying the time interval between surgery with immediate implant-based reconstruction and PMRT associated with lower probability of implant failure. Logistic regression models, Kaplan-Meier estimates and Polynomial regression were used to assess endpoints. RESULTS: The median follow-up was 43.5 months. 29.3%, 28.3% and 42.4% of the cohort had AR, TE/I and single-stage-direct-to-implant D, respectively. The 5-year cumulative incidence rate of complications was 14.0%, 29.7% and 19.4% for AR, TE/I and single-stage-direct-to-implant, respectively (Log rank p = 0.02). Multivariate analysis showed significant association between TE/I and higher risk of infection (OR 8.1, p = 0.009) compared to AR, while single-stage-direct-to-implant and AR were comparable (OR 3.2, p = 0.2). On subgroup analysis, TE/I was significantly associated with higher rates of implant failure. The mean wait time to deliver PMRT after immediate reconstruction with no adjuvant chemotherapy was 8.4 and 10.7 weeks in single-stage-direct-to-implant and TE/I, respectively (p < 0.005). Delivering PMRT after 8 weeks of surgery yielded 10% probability of reconstruction failure in single-stage-direct-to-implant versus 40% in TE/I. CONCLUSION: In comparison to two stages reconstruction, single-stage-direct-to-implant following neoadjuvant chemotherapy has lower complications and offers timely delivery of PMRT.

2.
Clin Cancer Res ; 2020 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-32571788

RESUMO

PURPOSE: Plasma genotyping may identify mutations in potentially "actionable" cancer genes, such as BRCA1/2, but their clinical significance is not well defined. We evaluated the characteristics of somatically acquired BRCA1/2 mutations in patients with MBC. METHODS: Patients with MBC undergoing routine cell-free DNA (cfDNA) next generation sequencing (73 gene panel) before starting a new therapy were included. Somatic BRCA1/2 mutations were classified as known germline-pathogenic mutations or novel variants, and linked to clinicopathological characteristics. The effect of the PARP inhibitor olaparib was assessed in vitro, using cultured circulating tumor cells (CTCs) from a patient with a somatically acquired BRCA1 mutation and a second patient with an acquired BRCA2 mutation. RESULTS: Among 215 MBC patients, 29 (13.5%) had somatic cfDNA BRCA1/2 mutations (nine (4%) known germline-pathogenic and rest (9%) novel variants). Known germline-pathogenic BRCA1/2 mutations were common in younger patients (p=0.008), those with triple-negative disease (p=0.022), and they were more likely to be protein-truncating alterations and be associated with TP53 mutations. Functional analysis of a CTC culture harboring a somatic BRCA1-mutation demonstrated high sensitivity to PARP inhibition, while another CTC culture harboring a somatic BRCA2 mutation showed no differential sensitivity. Across the entire cohort, APOBEC mutational signatures (COSMIC Signatures 2 and 13) and the "BRCA" mutational signature (COSMIC Signature 3) were present in BRCA1/2 mutant and wild-type cases, demonstrating the high mutational burden associated with advanced MBC. CONCLUSION: Somatic BRCA1/2 mutations are readily detectable in MBC by cfDNA analysis, and may be present as both known germline-pathogenic and novel variants.

3.
Sci Rep ; 10(1): 6331, 2020 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-32286375

RESUMO

The paradigm for post-operative cavity radiation therapy has shifted to more targeted, less morbid approaches. Single-fraction or hypofractionated radiation therapy is a common approach to treating the postoperative cavity but is associated with a local failure rate 20-40%. We employed an alternative treatment strategy involving fractionated partial brain radiation therapy to the surgical cavity. Patients with brain metastases who underwent radiation treatment 30-42 Gy in 3 Gy/fraction regimens to surgical cavity were retrospectively identified. The 6-month and 12-month freedom from local failure rates were 97.0% and 88.2%. Three patients (7%) experienced local failure at 4, 6, and 22 months. Of these, the histologies were colorectal adenocarcinoma (N = 1) and breast adenocarcinoma (N = 2). The 6-month and 12-month freedom from distant brain metastases rates were 74.1% and 68.8%, respectively, and the 6-month and 12-month overall survival rates were 84.9% and 64.3% respectively. The median overall survival was 39 months, and there were no events of late radionecrosis. Fractionated partial brain irradiation to the surgical cavity of resected brain metastases results in low rates of local failure. This strategy represents an alternative to SRS and WBRT.

4.
J Neurooncol ; 148(1): 81-88, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32307637

RESUMO

PURPOSE: Cranial irradiation results in cognitive decline, which is hypothesized to be partially attributable to hippocampal injury and stem cell loss. Recent advances allow for targeted reduction of radiation dose to the hippocampi while maintaining adequate dose coverage to the brain parenchyma and additional increasing dose to brain metastases, a approach called hippocampal avoidance whole brain radiation therapy with a simultaneous integrated boost (HA-WBRT + SIB.) We review our early clinical experience with HA-WBRT + SIB. MATERIALS AND METHODS: We evaluated treatments and clinical outcomes for patients treated with HA-WBRT + SIB between 2014 and 2018. RESULTS: A total of 32 patients (median age, 63.5 years, range 45.3-78.8 years) completed HA-WBRT + SIB. Median follow-up for patients alive at the time of analysis was 11.3 months. The most common histology was non-small cell lung cancer (n = 22). Most patients (n = 25) were prescribed with WBRT dose of 30 Gy with SIB to 37.5 Gy in 15 fractions. Volumetric modulated arc therapy reduced treatment time (p < 0.0001). Median freedom from intracranial progression and overall survival from completion of treatment were 11.4 months and 19.6 months, respectively. Karnofsky Performance Status was associated with improved survival (p = 0.008). The most common toxicities were alopecia, fatigue, and nausea. Five patients developed cognitive impairment, including grade 1 (n = 3), grade 2 (n = 1), and grade 3 (n = 1). CONCLUSION: HA-WBRT + SIB demonstrated durable intracranial disease control with modest side effects and merits further investigation as a means of WBRT toxicity reduction while improving long-term locoregional control in the brain.

5.
J Med Imaging Radiat Sci ; 51(1): 40-46, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31839482

RESUMO

PURPOSE: The logistical burdens of appointment scheduling and travel add to the psychological and emotional distress among patients with a new cancer diagnosis. This may be heightened among patients needing radiation therapy (RT), who must travel to and from a treatment facility daily for several weeks. Here, we studied the association between RT appointment waiting time and patient-reported pain and anxiety and explored additional factors that may influence daily waiting time. METHODS: Ninety-four patients undergoing RT at a single, academic institution were surveyed in the first and final weeks of treatment. On the day of the survey, patients were asked to report: pain (Likert scale: 0-10), anxiety (0-10), commute mode/time, and estimated waiting time for RT. Actual waiting times were calculated per review of the electronic scheduling system. RESULTS: Increased objective waiting time was associated with higher pain scores at the start (P = .05) and end (P = 0.004) of RT, although overall pain scores were low at both time points (mean 1.4 and 1.5, respectively). Anxiety scores were also low (mean 1.2 at both time points) and were not associated with objective waiting time (P > .05). Of note, patients reported perceived waiting times that were considerably shorter than actual waiting times (mean 15 vs. 26 minutes, respectively, at first survey early in the RT course). Time of day and tumor site were not associated with waiting time. CONCLUSION: Daily waiting time may play a role in pain and/or anxiety experienced by patients with cancer during RT. Perceived waiting time may differ substantially from actual waiting time and represents a potential area for intervention to improve patients' quality of life.

6.
World Neurosurg ; 133: e804-e812, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31605839

RESUMO

BACKGROUND: Histopathological grading of meningiomas is insufficient for optimal risk stratification. The purpose of the present study was to determine the prognostic value of atypical histopathological features across all nonmalignant meningiomas (World Health Organization [WHO] grade I-II). METHODS: The data from 334 patients with WHO grade I (n = 275) and grade II (n = 59) meningiomas who had undergone surgical resection from 2001 to 2015 at 2 academic centers were pooled. Progression/recurrence (P/R) was determined radiographically and measured from the date of surgery. RESULTS: The median follow-up was 52 months. The patients were stratified by the number of atypical features: 0 (n = 151), 1 (n = 71), 2 (n = 66), 3 (n = 22), and 4 or 5 (n = 24). The risk of P/R increased with an increasing number of atypical features (log-rank test, P = 0.001). The 5-year actuarial rates of P/R stratified by the number of atypical features were as follows: 0, 16.3% (95% confidence interval [CI], 10.7-24.4); 1, 21.7% (95% CI, 12.8-35.2); 2, 28.2% (95% CI, 18.4-41.7); 3, 30.4% (95% CI, 13.8-58.7); and 4 or 5, 51.4% (95% CI, 31.7-74.5). On univariate analysis, the presence of high nuclear/cytoplasmic ratio (P = 0.007), prominent nucleoli (P = 0.007), and necrosis (P < 0.00005) were associated with an increased risk of P/R. On multivariate analysis, the number of atypical features (hazard ratio [HR], 1.30; 95% CI, 1.03-1.63; P = 0.03), ≥4 mitoses per high-power fields (HR, 2.45; 95% CI, 1.17-5.15; P = 0.02), subtotal resection (HR, 3.9; 95% CI, 2.5-6.3; P < 0.0005), and the lack of adjuvant radiotherapy (HR, 2.40; 95% CI, 1.19-4.80; P = 0.01) were associated with an increased risk of P/R. CONCLUSIONS: An increased number of atypical features, ≥4 mitoses per 10 high-power fields, subtotal resection, and the lack of adjuvant radiotherapy were independently associated with P/R of WHO grade I-II meningiomas. Patients with these features might benefit from intensified therapy.


Assuntos
Neoplasias Meníngeas/cirurgia , Meningioma/cirurgia , Progressão da Doença , Feminino , Humanos , Masculino , Neoplasias Meníngeas/patologia , Neoplasias Meníngeas/radioterapia , Meningioma/patologia , Meningioma/radioterapia , Gradação de Tumores , Prognóstico , Radioterapia Adjuvante , Estudos Retrospectivos , Fatores de Risco , Falha de Tratamento
7.
Radiother Oncol ; 142: 154-161, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31563411

RESUMO

BACKGROUND AND PURPOSE: High-dose fractionated radiotherapy is often necessary to achieve long-term tumor control in several types of tumors involving or within close proximity to the brain. There is limited data to guide on optimal constraints to the adjacent nontarget brain. This investigation explored the significance of the three-dimensional (3D) dose distribution of passive scattering proton therapy to the brain with other clinicopathological factors on the development of symptomatic radiation necrosis. MATERIALS AND METHODS: All patients with head and neck, skull base, or intracranial tumors who underwent proton therapy (minimum prescription dose of 59.4 Gy(RBE)) with collateral moderate to high dose radiation exposure to the nontarget brain were retrospectively reviewed. A mixture cure model with respect to necrosis-free survival was used to derive estimates for the normal tissue complication probability (NTCP) model while adjusting for potential confounding factors. RESULTS: Of 179 identified patients, 83 patients had intracranial tumors and 96 patients had primary extracranial tumors. The optimal dose measure obtained to describe the occurrence of radiation necrosis was the equivalent uniform dose (EUD) with parameter a = 9. The best-fit parameters of logistic NTCP models revealed D50 = 57.7 Gy for intracranial tumors, D50 = 39.5 Gy for extracranial tumors, and γ50 = 2.5 for both tumor locations. Multivariable analysis revealed EUD and primary tumor location to be the strongest predictors of brain radiation necrosis. CONCLUSION: In the current clinical volumetric data analyses with multivariable modelling, EUD was identified as an independent and strong predictor for brain radiation necrosis from proton therapy.

8.
Int J Radiat Oncol Biol Phys ; 106(3): 514-524, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31756414

RESUMO

PURPOSE: To compare single-stage direct-to-implant (DTI) immediate reconstruction to the commonly used 2-stages expander and implant (TE/I) or autologous reconstruction with focus on postmastectomy radiation therapy (PMRT) setting. METHODS AND MATERIALS: We reviewed the charts of 1,286 patients who underwent 1,814 breast reconstructions at our institution with and without PMRT from 1997 to 2017. Patients were divided into 6 groups according to type of reconstruction and PMRT status. Primary objective was reconstruction complications defined solely on surgical reintervention operative notes such as infection, skin necrosis, and fat necrosis across all groups. Implant-related complications such as capsular contracture, implant rupture or exposure, or implant failure were compared between TE/I and DTI. Kaplan-Meier estimates were used to calculate 5-year cumulative incidence of complications. The secondary objective was to compare the 3 reconstruction types in settings of immediate reconstruction followed by PMRT on multivariable analysis. RESULTS: Median follow-up was 5.8 years. Among 1286 patients, 41.1% (N = 529/1286) received PMRT. Among 1814 reconstructed breasts, autologous, single-stage, and TE/I represented 18.7%, 34.8%, and 46.2%, respectively. With no PMRT, the 5-year cumulative incidence of any reconstruction complication was 11.1%, 12.6%, and 19.5% for autologous, DTI, and TE/I reconstructions, respectively. The addition of PMRT resulted in 5-year cumulative incidence of 15.1%, 18.2%, and 36.8%, respectively. The multivariable analysis showed that DTI was associated with lesser complications compared with TE/I, whereas no significant difference was noted between DTI and autologous. CONCLUSIONS: Single-stage DTI reconstruction had significantly lower complication rates than TE/I with and without PMRT. Single-stage complication rates were not significantly different from autologous complication rates in PMRT settings. Single-stage reconstruction may offer a valuable option for patients receiving PMRT.


Assuntos
Implante Mamário/efeitos adversos , Implantes de Mama/efeitos adversos , Neoplasias da Mama/radioterapia , Mamoplastia/efeitos adversos , Complicações Pós-Operatórias , Dispositivos para Expansão de Tecidos/efeitos adversos , Neoplasias da Mama/cirurgia , Feminino , Humanos , Incidência , Infecções/epidemiologia , Mamoplastia/métodos , Mamoplastia/estatística & dados numéricos , Pessoa de Meia-Idade , Necrose , Cuidados Pós-Operatórios , Complicações Pós-Operatórias/epidemiologia , Radioterapia Adjuvante/efeitos adversos , Radioterapia Adjuvante/estatística & dados numéricos , Estudos Retrospectivos , Pele/patologia , Pele/efeitos da radiação , Fatores de Tempo
9.
Head Neck ; 42(4): 670-677, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31850601

RESUMO

BACKGROUND: Although slow growing, head and neck paragangliomas (HNPG) can cause significant morbidity. We evaluated the efficacy of proton therapy in the management of HNPG. METHODS: Retrospective review of an institutional proton therapy experience of treating patients between 1997 and 2016; 37 patients and 40 tumors were included. RESULTS: Proton therapy was delivered to a median of 50.4 Gy(RBE) (range: 45-68). Having a genetic/family predisposition for HNPG was associated with multifocal tumors (P = .02) and younger diagnosis age (P = .02). Twenty-six (70%) patients had symptom improvement posttreatment, and 65% of treated tumors showed ≥20% volumetric shrinkage. The 5-year recurrence-free and overall survival rates were both 97%. Grade 2 to grade 3 toxicities (54%) included subjective hearing impairment (19%), middle ear inflammation (14%), and dry mouth (8%). There were no grade 4-5 toxicities. CONCLUSIONS: Patients with HNPGs can be effectively and safely treated with proton therapy with excellent tumor control, successful volumetric tumor reduction, and symptomatic improvement.

10.
Artigo em Inglês | MEDLINE | ID: mdl-31606528

RESUMO

Spinal cord tolerance data for stereotactic body radiation therapy (SBRT) were extracted from published reports, reviewed, and modelled. For de novo SBRT delivered in 1 to 5 fractions, the following spinal cord point maximum doses (Dmax) are estimated to be associated with a 1% to 5% risk of radiation myelopathy (RM): 12.4 to 14.0 Gy in 1 fraction, 17.0 Gy in 2 fractions, 20.3 Gy in 3 fractions, 23.0 Gy in 4 fractions, and 25.3 Gy in 5 fractions. For reirradiation SBRT delivered in 1 to 5 fractions, reported factors associated with a lower risk of RM include cumulative thecal sac equivalent dose in 2 Gy fractions with an alpha/beta of 2 (EQD22) Dmax ≤70 Gy; SBRT thecal sac EQD22 Dmax ≤25 Gy, thecal sac SBRT EQD22 Dmax to cumulative EQD22 Dmax ratio ≤0.5, and a minimum time interval to reirradiation of ≥5 months. Larger studies containing complete institutional cohorts with dosimetric data of patients treated with spine SBRT, with and without RM, are required to refine RM risk estimates.

11.
Clin Cancer Res ; 25(21): 6443-6451, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31371343

RESUMO

PURPOSE: While FGFR1 amplification has been described in breast cancer, the optimal treatment approach for FGFR1-amplified (FGFR1+) metastatic breast cancer (MBC) remains undefined.Experimental Design: We evaluated clinical response to endocrine and targeted therapies in a cohort of patients with hormone receptor-positive (HR+)/HER2- MBC and validated the functional role of FGFR1-amplification in mediating response/resistance to hormone therapy in vitro. RESULTS: In the clinical cohort (N = 110), we identified that patients with FGFR1+ tumors were more likely to have progesterone receptor (PR)-negative disease (47% vs. 20%; P = 0.005), coexisting TP53 mutations (41% vs. 21%; P = 0.05), and exhibited shorter time to progression with endocrine therapy alone and in combination with CDK4/6 inhibitor, but not with a mTOR inhibitor (everolimus), adjusting for key prognostic variables in multivariate analysis. Furthermore, mTOR-based therapy resulted in a sustained radiological and molecular response in an index case of FGFR1+ HR+/HER2- MBC. In preclinical models, estrogen receptor-positive (ER+)/FGFR1-amplified CAMA1 human breast cancer cells were only partially sensitive to fulvestrant, palbociclib, and alpelisib, but highly sensitive to everolimus. In addition, transduction of an FGFR1 expression vector into ER+ T47D cells induced resistance to fulvestrant that could be overcome by added TORC1 inhibition, but not PI3K or CDK4/6 inhibition. CONCLUSIONS: Collectively, these findings suggest that while FGFR1 amplification confers broad resistance to ER, PI3K, and CDK4/6 inhibitors, mTOR inhibitors might have a unique therapeutic role in the treatment of patients with ER+/FGFR1+ MBC.

12.
NPJ Precis Oncol ; 3: 18, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31341951

RESUMO

Plasma genotyping identifies potentially actionable mutations at variable mutant allele frequencies, often admixed with multiple subclonal variants, highlighting the need for their clinical and functional validation. We prospectively monitored plasma genotypes in 143 women with endocrine-resistant metastatic breast cancer (MBC), identifying multiple novel mutations including HER2 mutations (8.4%), albeit at different frequencies highlighting clinical heterogeneity. To evaluate functional significance, we established ex vivo culture from circulating tumor cells (CTCs) from a patient with HER2-mutant MBC, which revealed resistance to multiple targeted therapies including endocrine and CDK 4/6 inhibitors, but high sensitivity to neratinib (IC50: 0.018 µM). Immunoblotting analysis of the HER2-mutant CTC culture line revealed high levels of HER2 expression at baseline were suppressed by neratinib, which also abrogated downstream signaling, highlighting oncogenic dependency with HER2 mutation. Furthermore, treatment of an index patient with HER2-mutant MBC with the irreversible HER2 inhibitor neratinib resulted in significant clinical response, with complete molecular resolution of two distinct clonal HER2 mutations, with persistence of other passenger subclones, confirming HER2 alteration as a driver mutation. Thus, driver HER2 mutant alleles that emerge during blood-based monitoring of endocrine-resistant MBC confer novel therapeutic vulnerability, and ex vivo expansion of viable CTCs from the blood circulation may broadly complement plasma-based mutational analysis in MBC.

13.
Am J Clin Oncol ; 42(7): 564-572, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31166209

RESUMO

OBJECTIVES: Most localized hepatocellular carcinoma (HCC) patients are not surgically operable or transplantation candidates, increasing the role for nonsurgical therapies. Ablative external beam radiotherapy (XRT) and transarterial radioembolization (TARE) are emerging radiotherapeutic treatments for localized HCC. We sought to evaluate their utilization and efficacy in a large nationwide cohort. MATERIALS AND METHODS: We conducted an observational study of 2685 patients from the National Cancer Database (NCDB) diagnosed with American Joint Committee on Cancer 7th edition clinical stage I to III HCC between 2004 and 2015, treated with definitive-intent XRT delivered in 1 to 15 fractions or TARE. The association between treatment modality (XRT vs. TARE) and overall survival (OS) was defined using propensity score-weighted Kaplan-Meier estimators and propensity score-weighted multivariable Cox regressions. RESULTS: Among 2685 patients, 2007 (74.7%) received TARE and 678 (25.3%) received XRT, with increasing usage for both from 2004 to 2015 (Ptrend<0.001), but with overall greater uptake and absolute usage of TARE. Patients who received TARE were more likely to have elevated alpha fetoprotein and more advanced stage (P<0.05 for all). Median OS was 14.5 months for the entire cohort. XRT was associated with an OS advantage compared with TARE on propensity score-unadjusted analysis (adjusted hazard ratio [AHR], 0.89; 95% confidence interval, 0.79-1.00; P=0.049), but not on propensity score-adjusted analysis (AHR, 0.99; 95% confidence interval, 0.86-1.13; P=0.829). CONCLUSIONS: Our study demonstrates that while both XRT and TARE usage have increased with time, there was greater uptake and absolute use of TARE. We found no difference in survival between XRT and TARE after propensity score adjustment.


Assuntos
Carcinoma Hepatocelular/terapia , Embolização Terapêutica/métodos , Neoplasias Hepáticas/terapia , Idoso , Braquiterapia , Carcinoma Hepatocelular/patologia , Bases de Dados Factuais , Fracionamento da Dose de Radiação , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Pontuação de Propensão , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Taxa de Sobrevida
14.
Pract Radiat Oncol ; 9(3): e266-e273, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30731274

RESUMO

PURPOSE: Patients undergoing cranial irradiation are at high risk for development of subsequent pituitary deficiencies. Patients with meningiomas can expect to live many years after treatment and are therefore particularly vulnerable to long-term sequalae of radiation therapy (RT). The purpose of this study was to determine the rates and timing of onset of pituitary dysfunction across each hypothalamic-pituitary axis in patients with meningiomas in the sellar region. METHODS AND MATERIALS: Data from 74 patients with meningiomas in the sellar or perisellar region who underwent RT between 2001 and 2017 at a single academic center were analyzed. Dose-volume histograms were generated to determine the dose of radiation to the pituitary gland. Pituitary function tests were evaluated before and after completion of RT. RESULTS: There was a 20% risk for new hypopituitarism across any hypothalamic-pituitary axis after RT at a median follow-up of 43 months. Identified rates of dysfunction across each axis were 24% for thyroid and adrenal, 19% for growth hormone, and 10% for gonadal. Median time to develop deficiencies ranged from 11 months for growth hormone deficiency to 32 months for adrenal insufficiency. Deficiencies were likely to be correlated, with increased risk for thyroid dysfunction in patients with adrenal, gonadal, or prolactin deficiencies (P < .05). On univariate analysis, mean dose to the pituitary gland and male sex were associated with increased risk for post-RT thyroid deficiency (P = .01 and P = .004, respectively). There was no difference in rates of hypothyroidism after protons compared with photons (P = .14). CONCLUSIONS: Cranial irradiation for sellar meningiomas carries a risk for subsequent hypopituitarism that appears to be dose dependent and may occur years after completion of RT. Growth hormone deficiency and gonadal dysfunction were likely underestimated here secondary to a lack of routine testing. Given the favorable tumor prognosis in this patient population, early and long-term endocrine follow-up is warranted.


Assuntos
Irradiação Craniana/efeitos adversos , Hipopituitarismo/etiologia , Neoplasias Meníngeas/radioterapia , Meningioma/radioterapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Hipófise/fisiologia , Hipófise/efeitos da radiação , Lesões por Radiação/etiologia , Dosagem Radioterapêutica , Estudos Retrospectivos , Testes de Função Tireóidea
15.
Pract Radiat Oncol ; 9(4): e356-e361, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30790717

RESUMO

PURPOSE: Proton treatment may be a useful radiation therapy modality for long-term surviving patients with glioma to reduce normal tissue toxicities. Photon studies demonstrate that most low-grade glioma (LGG) failures occur within the radiation field, supporting the use of more conformal treatment plans, yet it is unclear whether this can be translated to proton radiation therapy (PRT). Our objective is to examine our institutional experience to determine patterns of failure in patients with LGG with respect to the volume irradiated with PRT. METHODS AND MATERIALS: Patients with World Health Organization 2007 grade I to II or isocitrate dehydrogenase 1-positive mutation grade III LGG treated with PRT between 2005 and 2015 were retrospectively reviewed. Patients with documented local recurrences on magnetic resonance imaging after receipt of PRT underwent a comparison with the initial treatment plan dosimetry to evaluate patterns of failure. A total of 141 patients were included in the final cohort. RESULTS: The median follow-up time was 46.7 months (range, 2.8-144 months), and 5-year overall survival was 84%. The median PRT dose delivered was 54 Gy (relative biological effectiveness) (range, 45-60 Gy). There were 42 failures after PRT (30%). The median time to progression after treatment was 32.7 months (range, 4.8-93.6 months). Thirty-one patients (74%) failed in-field (defined as within the 95% isodose volume), 5 patients (12%) failed out-of-field, and 5 patients (12%) had marginal failures (defined as within the 50%-95% isodose volume). The 5-year freedom from progression after PRT was 60.1% (95% confidence interval, 48.7-70.0). The 5-year cumulative incidence of overall survival was 33% among those with recurrence after PRT and 96% among those without recurrence after PRT (P < .001). CONCLUSIONS: Of the patients with LGG who had documented failures after PRT, most recurred within the radiation field with few marginal failures, indicating that even with PRT, which often can have steeper dose gradients, coverage is adequate. Survival was poor for patients whose tumors recurred.


Assuntos
Neoplasias Encefálicas/radioterapia , Glioma/radioterapia , Terapia com Prótons/métodos , Adolescente , Adulto , Neoplasias Encefálicas/patologia , Criança , Feminino , Glioma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Dosagem Radioterapêutica , Adulto Jovem
16.
Radiother Oncol ; 131: 112-119, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30773177

RESUMO

INTRODUCTION: Radiation-induced optic neuropathy (RION) is a complication of radiation therapy (RT) that causes blindness. We aimed to define the tolerance of the anterior optic pathway to fractionated RT and identify risk factors for RION. MATERIALS/METHODS: Patients with chordoma or chondrosarcoma of the skull base treated with proton and photon therapy between 1983 and 2013, who received a minimum of 30 Gy (relative biologic effectiveness [RBE]) to the anterior optic pathway were assessed. Optic neuropathy with radiographic correlation occurring ≥6 months after completion of RT in the absence of tumor recurrence or other probable cause was diagnosed as RION. RESULTS: Of 514 patients, 17 developed RION. With median follow-up of 4.8 years, cumulative incidence of RION was 1% among patients receiving <59 Gy (RBE) and 5.8% among patients receiving ≥60 Gy (RBE) to the optic pathway. Higher maximum point dose to the optic pathway (subhazard ratio [SHR] = 1.2, 95% CI 1.05-1.2, p = 0.001), older age (SHR = 1.1, 95% CI 1.02-1.08, p < 0.0005), and female sex (SHR = 16.3, 95% CI 2.2-122.4, p = 0.007) were statistically significant risk factors for RION in multivariate analysis. CONCLUSION: In our study cohort, rates of RION were very low with conventionally fractionated RT up to 59 Gy. At doses ≥60 Gy, there is an increased risk of RION, with greater risk for women and older patients.


Assuntos
Doenças do Nervo Óptico/etiologia , Nervo Óptico/efeitos da radiação , Fótons/efeitos adversos , Terapia com Prótons/efeitos adversos , Lesões por Radiação/etiologia , Adulto , Idoso , Condrossarcoma/radioterapia , Cordoma/radioterapia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Fótons/uso terapêutico , Terapia com Prótons/métodos , Tolerância a Radiação , Planejamento da Radioterapia Assistida por Computador , Estudos Retrospectivos , Fatores de Risco , Neoplasias Cranianas/radioterapia
17.
Med Phys ; 46(3): e53-e78, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30661238

RESUMO

The biological effectiveness of proton beams relative to photon beams in radiation therapy has been taken to be 1.1 throughout the history of proton therapy. While potentially appropriate as an average value, actual relative biological effectiveness (RBE) values may differ. This Task Group report outlines the basic concepts of RBE as well as the biophysical interpretation and mathematical concepts. The current knowledge on RBE variations is reviewed and discussed in the context of the current clinical use of RBE and the clinical relevance of RBE variations (with respect to physical as well as biological parameters). The following task group aims were designed to guide the current clinical practice: Assess whether the current clinical practice of using a constant RBE for protons should be revised or maintained. Identifying sites and treatment strategies where variable RBE might be utilized for a clinical benefit. Assess the potential clinical consequences of delivering biologically weighted proton doses based on variable RBE and/or LET models implemented in treatment planning systems. Recommend experiments needed to improve our current understanding of the relationships among in vitro, in vivo, and clinical RBE, and the research required to develop models. Develop recommendations to minimize the effects of uncertainties associated with proton RBE for well-defined tumor types and critical structures.


Assuntos
Neoplasias/radioterapia , Terapia com Prótons , Planejamento da Radioterapia Assistida por Computador/métodos , Planejamento da Radioterapia Assistida por Computador/normas , Eficiência Biológica Relativa , Humanos , Guias de Prática Clínica como Assunto/normas , Dosagem Radioterapêutica , Relatório de Pesquisa
18.
Cancer ; 125(8): 1357-1364, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30602061

RESUMO

BACKGROUND: Up to one-third of patients with localized Ewing sarcoma (ES) develop recurrent disease, but current biomarkers do not accurately identify this high-risk group. Therefore, the objective of this study was to determine the utility of mutational burden in predicting outcomes in patients with localized ES. METHODS: Clinical and genomic data from 99 patients with ES, of whom 63 had localized disease at diagnosis, were obtained from the cBioPortal for Cancer Genomics. Genomic data included the type and number of somatic mutations using cBioPortal mutation calling. Primary endpoints were overall survival (OS) and the time to progression (TTP). RESULTS: Patients had a median number of 11 somatic mutations. Patients were stratified according to whether they had a lower or higher mutational burden if they had ≤11 or >11 mutations, respectively. Higher mutational burden was significantly associated with inferior OS and TTP, a finding that was confirmed by univariate and multivariable analyses. In patients who had localized disease at diagnosis, higher mutational burden was the only variable significantly associated with inferior OS and TTP. The presence of a mutation in either stromal antigen 2 (STAG2) or tumor protein 53 (TP53), both of which were correlated previously with shorter OS in patients with ES, were significantly associated with higher mutational burden. Upon stratifying patients who had localized disease based on a standard panel of cancer genes, higher risk stratification was correlated significantly with inferior TTP and trended toward significance with inferior OS. CONCLUSIONS: Patients who have localized ES and a higher mutational burden have inferior OS and TTP compared with those who have lower mutation burden. The current findings suggest that the somatic mutation burden can be used to better risk stratify these patients and to guide clinical decision making.


Assuntos
Neoplasias Ósseas/genética , Proteínas de Ciclo Celular/genética , Mutação , Sarcoma de Ewing/genética , Proteína Supressora de Tumor p53/genética , Adolescente , Biomarcadores Tumorais/genética , Feminino , Humanos , Masculino , Prognóstico , Medição de Risco , Análise de Sobrevida
19.
J Neurooncol ; 142(1): 69-77, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30488294

RESUMO

INTRODUCTION: Concurrent radiotherapy and temozolomide (TMZ) is associated with radiographic pseudoprogression (PsP) in glioblastoma. The occurrence of PsP and other treatment effects is less well understood in low-grade gliomas (LGG). The purpose of this study is to evaluate whether the addition of TMZ to radiotherapy increases the incidence of PsP in adults with LGG treated with proton radiotherapy (PRT). METHODS: Chart review and volumetric MRI-analysis was performed on radiotherapy-naive adults with WHO grade II or IDH mutant WHO grade III gliomas treated with PRT between 2005 and 2015. Progression was defined by histology, new chemotherapy initiation, or progressive increase in lesion volume beyond 40% from baseline. Post treatment related effects (PTRE) were defined as new/increased T2/FLAIR or abnormal enhancement which eventually resolved or stabilized without evidence of progression for a period of 6-12 months. PsP was defined as the subset of PRTE suspicious for progression or volumetrically increased at least 40% from baseline. Pearson's chi-squared test and Cox-proportional hazards models were used for statistical analysis. RESULTS: There were 119 patients meeting inclusion criteria. There was an increased risk of PsP following PRT + TMZ versus PRT-alone (HR = 2.2, p = 0.006, on Cox univariate analysis). Presence of PsP was associated with improved OS (p = 0.02 with PsP as time-varying covariate). CONCLUSIONS: TMZ use, when added to PRT, was associated with increased PsP in patients with LGG; however, patients with PsP tended to achieve longer survival.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/terapia , Glioma/terapia , Terapia com Prótons , Temozolomida/uso terapêutico , Adolescente , Adulto , Idoso , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Terapia Combinada , Progressão da Doença , Feminino , Glioma/diagnóstico por imagem , Glioma/tratamento farmacológico , Glioma/radioterapia , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Adulto Jovem
20.
Breast Cancer Res Treat ; 174(1): 179-185, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30478787

RESUMO

PURPOSE: Patients with Her2-positive breast cancer treated with trastuzumab have higher rates of cardiotoxicity (CT). Left-breast radiation might increase the risk for CT from cardiac exposure to radiation. The goal of our study is to evaluate the contribution of radiotherapy (RT) in the development of CT in breast cancer patients receiving trastuzumab. METHODS: Two hundred and two patients were treated with RT and trastuzumab from 2000 to 2014. The RT plans for left-side disease were recalled from archives. The heart, each chamber, and left anterior descending artery (LAD) were independently contoured. New dose-volume histograms (DVH) were generated. Their serial left-ventricular ejection fractions (LVEF) were studied. CT for left and right side were compared using Fisher's exact test. The DVH data were correlated with the predefined cardiac events using actuarial Cox regression analysis. RESULTS: Compared to the right sided, the left-side cases showed statistically significant development of arrhythmia (14.2%) versus (< 1%) (p < 0.001). Cardiac ischemia was found in 10 patients in left and one patient in right side (p = 0.011). The equivalent uniform dose (EUD) to the left ventricle (LV), right ventricle (RV), and LAD was significantly associated with decrease in LVEF by > 10% (p = 0.037, p = 0.023 and p = 0.049, respectively). CONCLUSIONS: Among patients treated for left-sided lesions, there were no significant differences in EF decline. However, there was a higher rate of ischemia and arrhythmia compared to those with right-sided disease. The EUD index of LV, RV, and LAD could be considered as a parameter to describe the risk of radiation-induced CT.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/radioterapia , Cardiotoxicidade/etiologia , Quimiorradioterapia/efeitos adversos , Quimiorradioterapia/métodos , Adulto , Idoso , Antineoplásicos Imunológicos/efeitos adversos , Cardiotoxicidade/epidemiologia , Feminino , Humanos , Pessoa de Meia-Idade , Órgãos em Risco , Radioterapia/efeitos adversos , Trastuzumab/efeitos adversos
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