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PURPOSE: Uncertainties in postimplant quality assessment (QA) for low-dose-rate prostate brachytherapy (LDRPBT) are introduced at two steps: seed localization and contouring. We quantified how interobserver variability (IoV) introduced in both steps impacts dose-volume-histogram (DVH) parameters for MRI-based LDRPBT, and compared it with automatically derived DVH parameters. METHODS AND MATERIALS: Twenty-five patients received MRI-based LDRPBT. Seven clinical observers contoured the prostate and four organs at risk, and 4 dosimetrists performed seed localization, on each MRI. Twenty-eight unique manual postimplant QAs were created for each patient from unique observer pairs. Reference QA and automatic QA were also performed for each patient. IoV of prostate, rectum, and external urinary sphincter (EUS) DVH parameters owing to seed localization and contouring was quantified with coefficients of variation. Automatically derived DVH parameters were compared with those of the reference plans. RESULTS: Coefficients of variation (CoVs) owing to contouring variability (CoVcontours) were significantly higher than those due to seed localization variability (CoVseeds) (median CoVcontours vs. median CoVseeds: prostate D90-15.12% vs. 0.65%, p < 0.001; prostate V100-5.36% vs. 0.37%, p < 0.001; rectum V100-79.23% vs. 8.69%, p < 0.001; EUS V200-107.74% vs. 21.18%, p < 0.001). CoVcontours were lower when the contouring observers were restricted to the 3 radiation oncologists, but were still markedly higher than CoVseeds. Median differences in prostate D90, prostate V100, rectum V100, and EUS V200 between automatically computed and reference dosimetry parameters were 3.16%, 1.63%, -0.00 mL, and -0.00 mL, respectively. CONCLUSIONS: Seed localization introduces substantially less variability in postimplant QA than does contouring for MRI-based LDRPBT. While automatic seed localization may potentially help improve workflow efficiency, it has limited potential for improving the consistency and quality of postimplant dosimetry.
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Braquiterapia , Neoplasias da Próstata , Masculino , Humanos , Próstata/diagnóstico por imagem , Próstata/patologia , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/radioterapia , Neoplasias da Próstata/patologia , Incerteza , Braquiterapia/métodos , Dosagem Radioterapêutica , Tomografia Computadorizada por Raios X/métodos , Imageamento por Ressonância Magnética/métodosRESUMO
BACKGROUND AND PURPOSE: Proton therapy (PT) has emerged as a standard-of-care treatment option for localized prostate cancer at our comprehensive cancer center. However, there are few large-scale analyses examining the long-term clinical outcomes. Therefore, this article aims to evaluate the long-term effectiveness and toxicity of PT in patients with localized prostate cancer. MATERIALS AND METHODS: Review of 2772 patients treated from May 2006 through January 2020. Disease risk was stratified according to National Comprehensive Cancer Network guidelines as low [LR, n = 640]; favorable-intermediate [F-IR, n = 850]; unfavorable-intermediate [U-IR, n = 851]; high [HR, n = 315]; or very high [VHR, n = 116]. Biochemical failure and toxicity were analyzed using Kaplan-Meier estimates and multivariate models. RESULTS: The median patient age was 66 years; the median follow-up time was 7.0 years. Pelvic lymph node irradiation was prescribed to 28 patients (1%) (2 [0.2%] U-IR, 11 [3.5%] HR, and 15 [12.9%] VHR). The median dose was 78 Gy in 1.8-2.0 Gy(RBE) fractions. Freedom from biochemical relapse (FFBR) rates at 5 years and 10 years were 98.2% and 96.8% for the LR group; 98.3% and 93.6%, F-IR; 94.2% and 90.2%, U-IR; 94.3% and 85.2%, HR; and 86.1% and 68.5%, VHR. Two patients died of prostate cancer. Overall rates of late grade ≥ 3 GU and GI toxicity were 0.87% and 1.01%. CONCLUSIONS: Proton therapy for localized prostate cancer demonstrated excellent clinical outcomes in this large cohort, even among higher-risk groups with historically poor outcomes despite aggressive therapy.
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OBJECTIVES: To evaluate patients with clinical (c)T4 prostate cancer (PCa), which represent both a heterogenous and understudied population, who often present with locally advanced disease and obstructive symptoms causing significant morbidity and mortality. We analysed whether receiving definitive local therapy influenced symptomatic and oncological outcomes. METHODS: Retrospective analysis of 154 patients with cT4 PCa treated at a single institution in 1996-2020. Systemic therapy with or without local treatment (surgery, radiotherapy [RT], or both). Uni- and multivariate analyses of associations between clinicopathological features (including obstructive symptoms) and receipt of local therapy on overall survival (OS) and disease control were done with Cox regression. RESULTS: The median follow-up time was 5.9 years. Most patients had adenocarcinoma (88%), Gleason score 9-10 (77%), and median baseline prostate-specific antigen (PSA) of 20 ng/mL; most (54%) had metastatic cT4N0-1M1 disease; 24% regionally advanced cT4N1M0, and 22% localised cT4N0M0. Local therapies were RT (n = 44), surgery (n = 28), or both (n = nine). Local therapy was associated with improved OS (hazard ratio [HR] 0.3, P < 0.001), longer freedom from local recurrence (HR 0.39, P = 0.002), less local progression (HR 0.41, P = 0.02), fewer obstructive symptoms with progression (HR 0.31, P = 0.01), and less death from local disease (HR 0.25, P = 0.002). On multivariate, local therapy was associated with improved survival (HR 0.58, P = 0.02), and metastatic disease (HR 2.93, P < 0.001) or high-risk pathology (HR 2.05, P = 0.03) was associated with worse survival. CONCLUSION: Definitive local therapy for cT4 PCa was associated with improved symptomatic outcomes and survival even among men with metastatic disease. Pending prospective evaluation, these findings support definitive treatment with local therapy for cT4 disease in select cases.
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Adenocarcinoma , Neoplasias da Próstata , Masculino , Humanos , Estudos Retrospectivos , Neoplasias da Próstata/patologia , Antígeno Prostático Específico , Adenocarcinoma/terapia , Modelos de Riscos ProporcionaisRESUMO
BACKGROUND AND PURPOSE: Pd-103 and I-125 are commonly used in low dose rate (LDR) brachytherapy for prostate cancer. Comparisons of outcomes by isotope type are limited, but Pd-103 has distinct radiobiologic advantages over I-125 despite its lesser availability outside the United States. We evaluated oncologic outcomes after Pd-103 vs I-125 LDR monotherapy for prostate cancer. MATERIALS AND METHODS: We retrospectively analyzed databases at 8 institutions for men who received definitive LDR monotherapy with Pd-103 (n = 1,597) or I-125 (n = 7,504) for prostate cancer. Freedom from clinical failure (FFCF) and freedom from biochemical failure (FFBF) stratified by isotope were analyzed by Kaplan-Meier univariate and Cox multivariate analyses. Biochemical cure rates (prostate-specific antigen level ≤ 0.2 ng/mL between 3.5 and 4.5 years of follow-up) by isotype were calculated for men with at least 3.5 years of follow-up and compared by univariate and multivariate logistic regression. RESULTS: Compared with I-125, Pd-103 led to higher 7-year rates of FFBF (96.2% vs 87.6%, P < 0.001) and FFCF (96.5% vs 94.3%, P < 0.001). This difference held after multivariate adjustment for baseline factors (FFBF hazard ratio [HR] = 0.31, FFCF HR = 0.49, both P < 0.001). Pd-103 was also associated with higher cure rates on univariate (odds ratio [OR] = 5.9, P < 0.001) and multivariate (OR = 6.0, P < 0.001) analyses. Results retained significance in sensitivity analyses of data from the 4 institutions that used both isotopes (n = 2,971). CONCLUSIONS: Pd-103 monotherapy was associated with higher FFBF, FFCF, and biochemical cure rates, and suggests that Pd-103 LDR may lead to improved oncologic outcomes compared with I-125.
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Braquiterapia , Neoplasias da Próstata , Masculino , Humanos , Braquiterapia/métodos , Radioisótopos do Iodo/uso terapêutico , Próstata , Paládio/uso terapêutico , Estudos Retrospectivos , Dosagem Radioterapêutica , Neoplasias da Próstata/radioterapia , Neoplasias da Próstata/tratamento farmacológico , Antígeno Prostático Específico , SeguimentosRESUMO
The segmentation of the prostate and surrounding organs at risk (OARs) is a necessary workflow step for performing dose-volume histogram analyses of prostate radiation therapy procedures. Low-dose-rate prostate brachytherapy (LDRPBT) is a curative prostate radiation therapy treatment that delivers a single fraction of radiation over a period of days. Prior studies have demonstrated the feasibility of fully convolutional networks to segment the prostate and surrounding OARs for LDRPBT dose-volume histogram analyses. However, performance evaluations have been limited to measures of global similarity between algorithm predictions and a reference. To date, the clinical use of automatic segmentation algorithms for LDRPBT has not been evaluated, to the authors' knowledge. The purpose of this work was to assess the performance of fully convolutional networks for prostate and OAR delineation on a prospectively identified cohort of patients who underwent LDRPBT by using clinically relevant metrics. Thirty patients underwent LDRPBT and were imaged with fully balanced steady-state free precession MRI after implantation. Custom automatic segmentation software was used to segment the prostate and four OARs. Dose-volume histogram analyses were performed by using both the original automatically generated contours and the physician-refined contours. Dosimetry parameters of the prostate, external urinary sphincter, and rectum were compared without and with the physician refinements. This study observed that physician refinements to the automatic contours did not significantly affect dosimetry parameters. Keywords: MRI, Neural Networks, Radiation Therapy, Radiation Therapy/Oncology, Genital/Reproductive, Prostate, Segmentation, Dosimetry Supplemental material is available for this article. © RSNA, 2022.
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BACKGROUND AND PURPOSE: Comparing deep learning (DL) algorithms to human interobserver variability, one of the largest sources of noise in human-performed annotations, is necessary to inform the clinical application, use, and quality assurance of DL for prostate radiotherapy. MATERIALS AND METHODS: One hundred fourteen DL algorithms were developed on 295 prostate MRIs to segment the prostate, external urinary sphincter (EUS), seminal vesicles (SV), rectum, and bladder. Fifty prostate MRIs of 25 patients undergoing MRI-based low-dose-rate prostate brachytherapy were acquired as an independent test set. Groups of DL algorithms were created based on the loss functions used to train them, and the spatial entropy (SE) of their predictions on the 50 test MRIs was computed. Five human observers contoured the 50 test MRIs, and SE maps of their contours were compared with those of the groups of the DL algorithms. Additionally, similarity metrics were computed between DL algorithm predictions and consensus annotations of the 5 human observers' contours of the 50 test MRIs. RESULTS: A DL algorithm yielded statistically significantly higher similarity metrics for the prostate than did the human observers (H) (prostate Matthew's correlation coefficient, DL vs. H: planning-0.931 vs. 0.903, p < 0.001; postimplant-0.925 vs. 0.892, p < 0.001); the same was true for the 4 organs at risk. The SE maps revealed that the DL algorithms and human annotators were most variable in similar anatomical regions: the prostate-EUS, prostate-SV, prostate-rectum, and prostate-bladder junctions. CONCLUSIONS: Annotation quality is an important consideration when developing, evaluating, and using DL algorithms clinically.
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Próstata , Neoplasias da Próstata , Algoritmos , Computadores , Humanos , Imageamento por Ressonância Magnética , Masculino , Variações Dependentes do Observador , Próstata/diagnóstico por imagem , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/radioterapia , Planejamento da Radioterapia Assistida por ComputadorRESUMO
BACKGROUND AND PURPOSE: Quantifying the interobserver variability (IoV) of prostate and periprostatic anatomy delineation on prostate MRI is necessary to inform its use for treatment planning, treatment delivery, and treatment quality assessment. MATERIALS AND METHODS: Twenty five prostate cancer patients underwent MRI-based low-dose-rate prostate brachytherapy (LDRPBT). The patients were scanned with a 3D T2-weighted sequence for treatment planning and a 3D T2/T1-weighted sequence for quality assessment. Seven observers involved with the LDRPBT workflow delineated the prostate, external urinary sphincter (EUS), seminal vesicles, rectum, and bladder on all 50 MRIs. IoV was assessed by measuring contour similarity metrics, differences in organ volumes, and differences in dosimetry parameters between unique observer pairs. Measurements from a group of 3 radiation oncologists (G1) were compared against those from a group consisting of the other 4 clinical observers (G2). RESULTS: IoV of the prostate was lower for G1 than G2 (Matthew's correlation coefficient [MCC], G1 vs. G2: planning-0.906 vs. 0.870, p < 0.001; postimplant-0.899 vs. 0.861, p < 0.001). IoV of the EUS was highest of all the organs for both groups, but was lower for G1 (MCC, G1 vs. G2: planning-0.659 vs. 0.402, p < 0.001; postimplant-0.684 vs. 0.398, p < 0.001). Large differences in prostate dosimetry parameters were observed (G1 maximum absolute prostate ΔD90: planning-76.223 Gy, postimplant-36.545 Gy; G1 maximum absolute prostate ΔV100: planning-13.927%, postimplant-8.860%). CONCLUSIONS: While MRI is optimal in the management of prostate cancer with radiation therapy, significant interobserver variability of the prostate and external urinary sphincter still exist.
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Braquiterapia , Neoplasias da Próstata , Computadores , Humanos , Imageamento por Ressonância Magnética , Masculino , Variações Dependentes do Observador , Órgãos em Risco/diagnóstico por imagem , Próstata/diagnóstico por imagem , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/radioterapia , Radiometria , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por ComputadorRESUMO
BACKGROUND: Multimodality therapy (MMT) is recommended for patients with resectable gastric cancer, but no single approach has been established as standard. Little is presently known about current national practice patterns and sequencing of MMT. METHODS: Retrospective cohort study of patients with gastric cancer aged 18 to 80 y in the National Cancer Database (2006-2014) with ≥T2 and/or node-positive disease (i.e., stage Ib to III) treated with MMT. Clinical nodal staging accuracy was ascertained among those treated with upfront surgery by comparing clinical and pathologic nodal staging. Multivariable Cox regression was used to evaluate the association between overall risk of death and MMT approach (i.e., radiation used versus not and treatment sequence). RESULTS: Among 5817 patients, 16.1% received perioperative MMT, 50.6% preoperative only, and 33.3% postoperative only. The sensitivity, specificity, positive predictive value, and negative predictive values of clinical nodal staging were 68.4%, 88.8%, 91.1%, and 62.7%, respectively. Current clinical nodal staging modalities understage 37.3% of clinically node-negative patients. Over time, radiation utilization decreased (74.3% in 2006 versus 53.9% in 2014; trend test, P < 0.001), perioperative MMT increased (8.9% versus 22.2%%; trend test, P < 0.001), and postoperative MMT decreased (43.1% versus 21.0%; trend test, P < 0.001). Neither type of MMT nor treatment sequence is associated with risk of death. CONCLUSIONS: One-third of patients with gastric cancer who are candidates to receive MMT are treated with upfront surgery. Given the high false negative rate of clinical nodal staging and high noncompletion rate of postoperative treatment, efforts should be directed at improving and optimizing preoperative therapy utilization.
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Adenocarcinoma/terapia , Gastrectomia/tendências , Metástase Linfática/terapia , Terapia Neoadjuvante/tendências , Neoplasias Gástricas/terapia , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Adjuvante/estatística & dados numéricos , Quimioterapia Adjuvante/tendências , Reações Falso-Negativas , Feminino , Gastrectomia/estatística & dados numéricos , Humanos , Estimativa de Kaplan-Meier , Linfonodos/patologia , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/estatística & dados numéricos , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Radioterapia Adjuvante/estatística & dados numéricos , Radioterapia Adjuvante/tendências , Sistema de Registros/estatística & dados numéricos , Estudos Retrospectivos , Estômago/patologia , Estômago/cirurgia , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Estados Unidos/epidemiologia , Adulto JovemRESUMO
INTRODUCTION: Chemotherapy and radiation therapy are two mainstream strategies applied in the treatment of cancer that is not operable. Patients with hematological or solid tumor malignancies substantially benefit from chemotherapeutic drugs and/or ionizing radiation delivered to the site of malignancy. However, considerable adverse effects, including lung inflammation and fibrosis, are associated with the use of these treatment modalities. Areas covered: As we move toward the era of precision health, we are compelled to understand the molecular basis of chemoradiation-induced pathological lung remodeling and to develop effective treatment strategies that mitigate the development of chronic lung disease (i.e. fibrosis) in cancer patients. The review discusses chemotherapeutic agents that are reported to induce or associate with acute and/or chronic lung injury. Expert commentary: There is a need to molecularly understand how chemotherapeutic drugs induce or associate with respiratory toxicities and whether such characteristics are inherently related to their antitumor effect or are collateral. Once such mechanisms have been identified and/or fully characterized, they may be able to guide disease-management decisions including effective intervention strategies for the adverse effects. In the meantime, radiation oncologists should be judicious on the dose of radiation delivered to the lungs, the volume of lung irradiated, and concurrent use of chemotherapeutic drugs.
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Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar/etiologia , Neoplasias/terapia , Lesão Pulmonar Aguda/fisiopatologia , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Quimiorradioterapia/efeitos adversos , Quimiorradioterapia/métodos , Humanos , Lesão Pulmonar/fisiopatologia , Neoplasias/patologiaRESUMO
Resection techniques for esophageal carcinoma continue to evolve, from endoscopic mucosal resection or endoscopic submucosal dissection for early stage disease to standard and robot-assisted minimally invasive esophagectomy as part of multimodal therapy for locally advanced disease. Though currently limited to assessing conduit perfusion and sentinel lymph nodes, embedded technology in the robotic surgical platform will likely play an expanded role during esophagectomy in the future. The use of targeted therapies, checkpoint inhibitors, engineered immune cell therapy, and cancer vaccines show promise in the treatment of systemic disease. Radiation therapy techniques are becoming increasingly sophisticated and they may play a more active role in stage IV disease in the future.
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OBJECTIVE: Metastatic spinal cord compression (MSCC) is an oncologic emergency that often warrants emergent treatment; but, it is unclear whether radiation treatment (RT) can be optimally managed from an offsite radiotherapy facility. METHODS: Patient charts from consecutive patients with MSCC who were treated with radiotherapy alone at either an onsite hospital radiation department (from 2008 to 2012) or an offsite radiotherapy centre (2012-2015) were reviewed. Patient clinical parameters were compared across groups with either the χ2 test or Fisher's exact test, while survival curves were compared with the log-rank test. The primary end points were ambulatory rate over time, overall survival and cancer-specific survival. RESULTS: A total of 45 patients were identified, with 19 patients treated onsite in the hospital department and 26 patients treated at the offsite radiotherapy centre with median follow-up of 42 days vs 48.5 days, respectively. The ambulatory rate over time, overall survival and cancer-specific survival were not significantly different between the two eras. Patients treated in-hospital were more likely to start treatment the same day as the consult ("sim and treat") (79% vs 27%, p = 0.006) and were more likely to not complete treatment (26% vs 4%, p = 0.029) as compared with those treated in the offsite centre. CONCLUSION: Patients with MSCC can be feasibly treated at an offsite radiotherapy centre with outcomes similar to those treated in-hospital. Advances in knowledge: This is the first study in literature to compare outcomes between onsite and offsite RT of MSCC.
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Instituições de Assistência Ambulatorial/estatística & dados numéricos , Serviço Hospitalar de Radiologia/estatística & dados numéricos , Compressão da Medula Espinal/radioterapia , Neoplasias da Coluna Vertebral/radioterapia , Assistência Ambulatorial/métodos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida , Resultado do TratamentoRESUMO
Curative-intent therapy for stage II/III rectal cancer is necessarily complex. Current guidelines by the National Comprehensive Cancer Network recommend preoperative concurrent chemoradiation followed by resection and additional adjuvant chemotherapy. We used standard quality improvement methodology to implement a cost-effective intervention that reduced the time from diagnosis to treatment of patients with stage II/III rectal cancer by approximately 30% in a large public hospital in Houston, Texas. Implementation of the program resulted in a reduction in time from pathologic diagnosis to treatment of 29% overall, from 62 to 44 days. These gains were cost neutral and resulted from improvements in scheduling and coordination of care alone. Our results suggest that: (1) quality improvement methodology can be successfully applied to multidisciplinary cancer care, (2) effective interventions can be cost neutral, and (3) effective strategies can overcome complexities such as having multiple sites of care, high staff turnover, and resource limitations.
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Hospitais Públicos , Neoplasias Retais/diagnóstico , Neoplasias Retais/terapia , Tempo para o Tratamento , Gerenciamento Clínico , Humanos , Estadiamento de Neoplasias , Indicadores de Qualidade em Assistência à Saúde , Qualidade da Assistência à Saúde , Texas , Fatores de TempoRESUMO
PURPOSE: Acute vulvitis, acute urethritis, and permanent sexual dysfunction are common among patients treated with chemoradiation for squamous cell carcinoma of the anal canal. Avoidance of the genitalia may reduce sexual dysfunction. A vaginal dilator may help delineate and displace the vulva and lower vagina away from the primary tumor. The goal of this study was to evaluate the positional reproducibility and vaginal sparing with the use of a vaginal dilator. MATERIALS AND METHODS: Ten female patients treated with IMRT for anal cancer were included in this study. A silicone vaginal dilator measuring 29 mm in diameter and 114 mm in length was inserted into the vagina before simulation and each treatment. The reproducibility of dilator placement was investigated with antero-posterior and lateral images acquired daily. Weekly cone beam CT (CBCT) imaging was used to confirm coverage of the GTV, which was typically posterior and inferior to the dilator apex. Finally, a planning study was performed to compare the vaginal doses for these 10 patients to a comparable group of 10 female patients who were treated for anal cancer with IMRT without vaginal dilators. RESULTS: The absolute values of the location of the dilator apex were 7.0 ± 7.8mm in the supero-inferior direction, 7.5 ± 5.5 mm in the antero-posterior, and 3.8 ± 3.1mm in the lateral direction. Coverage of the GTV and CTV was confirmed from CBCT images. The mean dose to the vagina was lower by 5.5 Gy, on average, for the vaginal dilator patients, compared to patients treated without vaginal dilators. CONCLUSION: The vaginal dilator tended to be inserted more inferiorly during treatment than during simulation. For these ten patients, this did not compromise tumor coverage. Combined with IMRT treatment planning, use of a vaginal dilator could allow for maximum sparing of female genitalia for patients undergoing radiation therapy for anal cancer.
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Neoplasias do Ânus/terapia , Carcinoma de Células Escamosas/terapia , Dilatação/instrumentação , Genitália Feminina/efeitos da radiação , Lesões por Radiação/prevenção & controle , Proteção Radiológica/instrumentação , Radioterapia de Intensidade Modulada/efeitos adversos , Idoso , Neoplasias do Ânus/mortalidade , Neoplasias do Ânus/patologia , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Quimiorradioterapia/efeitos adversos , Quimiorradioterapia/métodos , Tomografia Computadorizada de Feixe Cônico/métodos , Desenho de Equipamento , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Prospectivos , Doses de Radiação , Radioterapia de Intensidade Modulada/métodos , Reprodutibilidade dos Testes , Medição de Risco , Estudos de Amostragem , Análise de Sobrevida , Resultado do Tratamento , Vagina/diagnóstico por imagem , Vagina/efeitos da radiaçãoRESUMO
PURPOSE: The goal of this study was to evaluate dosimetric parameters, acute toxicity, pathologic response, and local control in patients treated with preoperative intensity-modulated radiation therapy (IMRT) and concurrent chemotherapy for localized gastric adenocarcinoma. METHODS: Between November 2007 and April 2010, 25 patients with localized gastric adenocarcinoma were treated with induction chemotherapy, followed by preoperative IMRT and concurrent chemotherapy and, finally, surgical resection. The median radiation therapy dose was 45 Gy. Concurrent chemotherapy was 5-fluorouracil and oxaliplatin in 18 patients, capecitabine in 3, and other regimens in 4. Subsequently, resection was performed with total gastrectomy in 13 patients, subtotal gastrectomy in 7, and other surgeries in 5. RESULTS: Target coverage, expressed as the ratio of the minimum dose received by 99% of the planning target volume to the prescribed dose, was a median of 0.97 (range, 0.92-1.01). The median V(30) (percentage of volume receiving at least 30 Gy) for the liver was 26%; the median V(20) (percentage of volume receiving at least 20 Gy) for the right and left kidneys was 14% and 24%, respectively; and the median V(40) (percentage of volume receiving at least 40 Gy) for the heart was 18%. Grade 3 acute toxicity developed in 14 patients (56%), including dehydration in 10, nausea in 8, and anorexia in 5. Grade 4 acute toxicity did not develop in any patient. There were no significant differences in the rates of acute toxicity, hospitalization, or feeding tube use in comparison to those in a group of 50 patients treated with preoperative three-dimensional conformal radiation therapy with concurrent chemotherapy. R0 resection was obtained in 20 patients (80%), and pathologic complete response occurred in 5 (20%). CONCLUSIONS: Preoperative IMRT for gastric adenocarcinoma was well tolerated, accomplished excellent target coverage and normal structure sparing, and led to appropriate pathologic outcomes.
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Adenocarcinoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimiorradioterapia/métodos , Radioterapia de Intensidade Modulada/métodos , Neoplasias Gástricas/terapia , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adulto , Idoso , Anorexia/etiologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Capecitabina , Quimiorradioterapia/efeitos adversos , Quimiorradioterapia/mortalidade , Desidratação/etiologia , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Docetaxel , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/análogos & derivados , Gastrectomia/métodos , Coração/efeitos da radiação , Humanos , Quimioterapia de Indução/efeitos adversos , Quimioterapia de Indução/métodos , Rim/efeitos da radiação , Masculino , Pessoa de Meia-Idade , Náusea/etiologia , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Cuidados Pré-Operatórios/métodos , Dosagem Radioterapêutica , Radioterapia de Intensidade Modulada/efeitos adversos , Estudos Retrospectivos , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Taxoides/administração & dosagem , Resultado do TratamentoRESUMO
BACKGROUND: A strong dose-volume relationship exists between the amount of small bowel receiving low- to intermediate-doses of radiation and the rates of acute, severe gastrointestinal toxicity, principally diarrhea. There is considerable interest in the application of highly conformal treatment approaches, such as intensity-modulated radiation therapy (IMRT), to reduce dose to adjacent organs-at-risk in the treatment of carcinoma of the rectum. Therefore, we performed a comprehensive dosimetric evaluation of IMRT compared to 3-dimensional conformal radiation therapy (3DCRT) in standard, preoperative treatment for rectal cancer. METHODS: Using RTOG consensus anorectal contouring guidelines, treatment volumes were generated for ten patients treated preoperatively at our institution for rectal carcinoma, with IMRT plans compared to plans derived from classic anatomic landmarks, as well as 3DCRT plans treating the RTOG consensus volume. The patients were all T3, were node-negative (N = 1) or node-positive (N = 9), and were planned to a total dose of 45-Gy. Pairwise comparisons were made between IMRT and 3DCRT plans with respect to dose-volume histogram parameters. RESULTS: IMRT plans had superior PTV coverage, dose homogeneity, and conformality in treatment of the gross disease and at-risk nodal volume, in comparison to 3DCRT. Additionally, in comparison to the 3DCRT plans, IMRT achieved a concomitant reduction in doses to the bowel (small bowel mean dose: 18.6-Gy IMRT versus 25.2-Gy 3DCRT; p = 0.005), bladder (V40Gy: 56.8% IMRT versus 75.4% 3DCRT; p = 0.005), pelvic bones (V40Gy: 47.0% IMRT versus 56.9% 3DCRT; p = 0.005), and femoral heads (V40Gy: 3.4% IMRT versus 9.1% 3DCRT; p = 0.005), with an improvement in absolute volumes of small bowel receiving dose levels known to induce clinically-relevant acute toxicity (small bowel V15Gy: 138-cc IMRT versus 157-cc 3DCRT; p = 0.005). We found that the IMRT treatment volumes were typically larger than that covered by classic bony landmark-derived fields, without incurring penalty with respect to adjacent organs-at-risk. CONCLUSIONS: For rectal carcinoma, IMRT, compared to 3DCRT, yielded plans superior with respect to target coverage, homogeneity, and conformality, while lowering dose to adjacent organs-at-risk. This is achieved despite treating larger volumes, raising the possibility of a clinically-relevant improvement in the therapeutic ratio through the use of IMRT with a belly-board apparatus.
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Adenocarcinoma/radioterapia , Carcinoma/radioterapia , Intestino Delgado/efeitos da radiação , Radiometria/métodos , Radioterapia de Intensidade Modulada/métodos , Neoplasias Retais/radioterapia , Relação Dose-Resposta à Radiação , Feminino , Humanos , Imageamento Tridimensional , Metástase Linfática , Masculino , Doses de Radiação , Proteção Radiológica/métodos , Planejamento da Radioterapia Assistida por Computador/métodosAssuntos
Química/educação , Proteínas/química , Bolsas de Estudo , Hong Kong , Engenharia de Proteínas , Reino Unido , UniversidadesRESUMO
PURPOSE: Volumetric modulated arc therapy (VMAT), an evolution of intensity modulated radiation therapy (IMRT), utilizes the dynamic modulation of angular dose rate through changes in gantry speed, linear accelerator dose rate, and multileaf collimator motion to deliver a treatment fraction in rotational fashion with improved efficiency and in shorter time. In general, target coverage relative to adjacent organ-at-risk sparing is highly dependent on the complexity of the treatment site. Therefore, we critically evaluated VMAT compared to IMRT for definitive treatment of anal carcinoma with respect to dosimetry and efficiency. METHODS AND MATERIALS: Using SmartArc (Philips Healthcare, Andover, MA), VMAT treatment plans were generated for 10 patients treated at our institution for anal carcinoma, and compared to the IMRT plans used for clinical treatment. The patients were all female, had T classification TX/1 (n = 5), T2 (n = 3) or T3 (n = 2), were node-negative (n = 6) or node-positive (n = 4), and were treated to a total dose of 50 to 58 Gy. Pairwise comparisons were made between VMAT and IMRT plans with respect to dose-volume histogram parameters relating the dose received by target volumes, relevant organs at risk, and normal tissues. The plans were machine-delivered, with actual beam delivery times measured. RESULTS: VMAT plans had superior planning target volume coverage and dose homogeneity, with improved conformality in treatment of the elective nodal volume, in comparison to IMRT. Mean dose to the small bowel, genitalia, and femoral heads were significantly lower with VMAT, and similar with respect to bladder, pelvic bones, and normal tissues. Integral dose was comparable between the 2 techniques. VMAT plans required 36.8% fewer monitor units, and beam delivery time was shorter by 9 minutes. CONCLUSIONS: Our results indicate that VMAT represents an ideal treatment modality for anal carcinoma, generating plans with excellent target coverage, lower doses to organs at risk, and shorter treatment times, in comparison to IMRT.
RESUMO
PURPOSE: It has been shown that valproic acid (VA) enhances the proliferation and self-renewal of normal hematopoietic stem cells and that breast cancer stem/progenitor cells can be resistant to radiation. From these data, we hypothesized that VA would fail to radiosensitize breast cancer stem/progenitor cells grown to three-dimensional (3D) mammospheres. METHODS AND MATERIALS: We used the MCF7 breast cancer cell line grown under stem cell-promoting culture conditions (3D mammosphere) and standard nonstem cell monolayer culture conditions (two-dimensional) to examine the effect of pretreatment with VA on radiation sensitivity in clonogenic survival assays and on the expression of embryonic stem cell transcription factors. RESULTS: 3D-cultured MCF-7 cells expressed higher levels of Oct4, Nanog, and Sox2. The 3D passage enriched self-renewal and increased radioresistance in the 3D mammosphere formation assays. VA radiosensitized adherent cells but radioprotected 3D cells in single-fraction clonogenic assays. Moreover, fractionated radiation sensitized VA-treated adherent MCF7 cells but did not have a significant effect on VA-treated single cells grown to mammospheres. CONCLUSION: We have concluded that VA might preferentially radiosensitize differentiated cells compared with those expressing stem cell surrogates and that stem cell-promoting culture is a useful tool for in vitro evaluation of novel cancer therapeutic agents and radiosensitizers.
Assuntos
Células-Tronco Neoplásicas/efeitos da radiação , Tolerância a Radiação/efeitos dos fármacos , Radiossensibilizantes/farmacologia , Ácido Valproico/farmacologia , Técnicas de Cultura de Células/métodos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células , Proteínas de Homeodomínio/metabolismo , Humanos , Proteína Homeobox Nanog , Células-Tronco Neoplásicas/citologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Fator 3 de Transcrição de Octâmero/metabolismo , Tolerância a Radiação/fisiologia , Protetores contra Radiação/farmacologia , Fatores de Transcrição SOXB1/metabolismo , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/metabolismo , Esferoides Celulares/patologia , Esferoides Celulares/efeitos da radiação , Ensaio Tumoral de Célula-Tronco/métodosRESUMO
The screening of a small focused library of rhodanine derivatives as inhibitors of Bcl-2 proteins led to the discovery of two structurally related compounds with different binding profiles against the Bcl-XL and the Mcl-1 proteins. Subsequent NMR studies with mutant proteins and in silico docking studies provide a possible rationale for the observed specificity.
Assuntos
Antineoplásicos/síntese química , Ciclina D1/metabolismo , Tiazolidinas/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Ciclina D1/antagonistas & inibidores , Ciclina D1/genética , Polarização de Fluorescência , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Mutagênese Sítio-Dirigida , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-Atividade , Tiazolidinas/química , Tiazolidinas/farmacologiaRESUMO
The type IVb pilus of the enteropathogenic bacteria Salmonella typhi is a major adhesion factor during the entry of this pathogen into gastrointestinal epithelial cells. Its target of adhesion is a stretch of 10 residues from the first extracellular domain of cystic fibrosis transmembrane conductance regulator (CFTR). The crystal structure of the N-terminal 25 amino acid deleted S. typhi native PilS protein (DeltaPilS), which makes the pilus, was determined at 1.9 A resolution by the multiwavelength anomalous dispersion method. Also, the structure of the complex of DeltaPilS and a target CFTR peptide, determined at 1.8 A, confirms that residues 113-117 (NKEER) of CFTR are involved in binding with the pilin protein and gives us insight on the amino acids that are essential for binding. Furthermore, we have also explored the role of a conserved disulfide bridge in pilus formation. The subunit structure and assembly architecture are crucial for understanding pilus functions and designing suitable therapeutics against typhoid.