RESUMO
PURPOSE: To determine the efficacy and toxicity of weekly neoadjuvant cetuximab combined with irinotecan, cisplatin, and radiation therapy in patients with locally advanced esophageal or gastroesophageal junction cancer. METHODS AND MATERIALS: Patients with stage IIA-IVA esophageal or gastroesophageal junction cancer were enrolled in a Simon's two-stage phase II study. Patients received weekly cetuximab on weeks 0-8 and irinotecan and cisplatin on weeks 1, 2, 4, and 5, with concurrent radiotherapy (50.4 Gy on weeks 1-6), followed by surgical resection. RESULTS: In the first stage, 17 patients were enrolled, 16 of whom had adenocarcinoma. Because of a low pathologic complete response (pCR) rate in this cohort, the trial was discontinued for patients with adenocarcinoma but squamous cell carcinoma patients continued to be enrolled; two additional patients were enrolled before the study was closed as a result of poor accrual. Of the 19 patients enrolled, 18 patients proceeded to surgery, and 16 patients underwent an R0 resection. Three patients (16%) had a pCR. The median progression-free survival interval was 10 months, and the median overall survival duration was 31 months. Severe neutropenia occurred in 47% of patients, and severe diarrhea occurred in 47% of patients. One patient died preoperatively from sepsis, and one patient died prior to hospital discharge following surgical resection. CONCLUSIONS: This schedule of cetuximab in combination with irinotecan, cisplatin, and radiation therapy was toxic and did not achieve a sufficient pCR rate in patients with localized esophageal adenocarcinoma to undergo further evaluation.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/radioterapia , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Camptotecina/análogos & derivados , Cetuximab , Quimiorradioterapia Adjuvante , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Neoplasias Esofágicas/cirurgia , Junção Esofagogástrica/patologia , Feminino , Humanos , Irinotecano , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Cuidados Pré-Operatórios , Estudos Prospectivos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/radioterapia , Neoplasias Gástricas/cirurgia , Adulto JovemRESUMO
PURPOSE: We investigated the metabolic response of lung cancer to radiotherapy or chemoradiotherapy by (18)F-FDG PET and its utility in guiding timely supplementary therapy. METHODS: Glucose metabolic rate (MRglc) was measured in primary lung cancers during the 3 weeks before, and 10-12 days (S2), 3 months (S3), 6 months (S4), and 12 months (S5) after radiotherapy or chemoradiotherapy. The association between the lowest residual MRglc representing the maximum metabolic response (MRglc-MMR) and tumor control probability (TCP) at 12 months was modeled using logistic regression. RESULTS: We accrued 106 patients, of whom 61 completed the serial (18)F-FDG PET scans. The median values of MRglc at S2, S3 and S4 determined using a simplified kinetic method (SKM) were, respectively, 0.05, 0.06 and 0.07 µmol/min/g for tumors with local control and 0.12, 0.16 and 0.19 µmol/min/g for tumors with local failure, and the maximum standard uptake values (SUVmax) were 1.16, 1.33 and 1.45 for tumors with local control and 2.74, 2.74 and 4.07 for tumors with local failure (p < 0.0001). MRglc-MMR was realized at S2 (MRglc-S2) and the values corresponding to TCP 95 %, 90 % and 50 % were 0.036, 0.050 and 0.134 µmol/min/g using the SKM and 0.70, 0.91 and 1.95 using SUVmax, respectively. Probability cut-off values were generated for a given level of MRglc-S2 based on its predicted TCP, sensitivity and specificity, and MRglc ≤0.071 µmol/min/g and SUVmax ≤1.45 were determined as the optimum cut-off values for predicted TCP 80 %, sensitivity 100 % and specificity 63 %. CONCLUSION: The cut-off values (MRglc ≤0.071 µmol/min/g using the SKM and SUVmax ≤1.45) need to be tested for their utility in identifying patients with a high risk of residual cancer after standard dose radiotherapy or chemoradiotherapy and in guiding a timely supplementary dose of radiation or other means of salvage therapy.
Assuntos
Quimiorradioterapia , Fluordesoxiglucose F18 , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/radioterapia , Tomografia por Emissão de Pósitrons , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Glucose/metabolismo , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Pessoa de Meia-Idade , Probabilidade , Estudos Prospectivos , Análise de Regressão , Sensibilidade e Especificidade , Resultado do TratamentoRESUMO
BACKGROUND: This study examined the association between functional single-nucleotide polymorphisms in candidate genes from oxidative stress pathways and risk of radiation pneumonitis (RP) in patients treated with thoracic radiation therapy for locally advanced lung cancer. METHODS: A review was conducted of 136 patients treated with radiation therapy for lung cancer between 2001 and 2007, and who had prior genotyping of functional single-nucleotide polymorphisms in oxidative stress genes including superoxide dismutase 2 (SOD2; rs4880) and methylene tetrahydrofolate reductase (MTHFR; rs1801131, rs1801133). RP events were retrospectively scored using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Cox proportional hazard regression was performed to identify clinical variables and genotypes associated with risk of RP of grades ≥2 and ≥3 on univariate and multivariate analysis, respectively. P values were corrected for multiple hypothesis esting. RESULTS: With a median follow-up of 21.4 months, the incidence of grade ≥2 RP was 29% and grade ≥3 RP was 14%. On multivariate analysis, after adjusting for clinical factors such as concurrent chemotherapy and consolidation docetaxel, and lung dosimetric parameters such as volume receiving greater than 20 Gy and mean lung dose, MTHFR genotype (rs1801131; AA versus AC/CC) was significantly associated with risk of grade ≥2 RP (hazard ratio: 0.37; 95% confidence interval: 0.18-0.76; P = .006, corrected P = .018) and grade ≥3 RP (hazard ratio: 0.21; 95% confidence interval: 0.06-0.70; P = .01; corrected P = .03). SOD2 genotype was not associated with RP. CONCLUSIONS: This study showed an association between MTHFR genotype and risk of clinically significant RP. Further study of MTHFR-related pathways may provide insight into the mechanisms behind RP.
Assuntos
Neoplasias Pulmonares/genética , Neoplasias Pulmonares/radioterapia , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo de Nucleotídeo Único , Pneumonite por Radiação/genética , Radioterapia/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doses de Radiação , Radioterapia/métodos , Risco , Fatores de RiscoRESUMO
PURPOSE: To compare (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) and computed tomography (CT) imaging characteristics in non-small cell lung cancer (NSCLC) with or without epidermal growth factor receptor (EGFR) mutations. METHODS: We retrospectively identified NSCLC patients who underwent EGFR mutation testing and pretreatment FDG-PET and CT scans. The maximum standard uptake value (SUV(max)) of the primary tumor and any metastases was measured and normalized to the SUV of blood in the pulmonary artery. We compared normalized SUV(max) values between EGFR-mutant and wild-type patients and modeled radiographic and clinical predictors of EGFR mutation status. Receiver operator characteristic (ROC) curves were used to identify potential SUV cutoffs predictive of genotype. RESULTS: We included 100 patients (24 EGFR-mutant and 76 wild-type). There was a trend for higher normalized SUV(max) in the primary tumors among patients with EGFR-wild-type versus mutant (median, 3.4; range, 0.6-12.8; versus median, 2.9; range, 0.4-5.0; p = .09). Normalized SUV(max) of nodal and distant metastases, and CT characteristics were not associated with genotype. On multivariate analysis, low normalized SUV(max) of the primary tumor was predictive for EGFR mutation (odds ratio, 0.72; 95% confidence interval, 0.53-0.98; p = .034). ROC curve analyses yielded an area under the curve of 0.62, and identified a potential cutoff of ≥ 5.0 to distinguish wild-type from mutant tumors. CONCLUSIONS: In this retrospective study, high FDG avidity (normalized SUV(max) ≥ 5) correlated with EGFR-wild-type genotype. Although genotyping remains the gold standard, further work to validate FDG-PET as a surrogate for tumor genotype may provide useful information in patients without available tumor tissue.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Receptores ErbB/genética , Fluordesoxiglucose F18 , Neoplasias Pulmonares/diagnóstico por imagem , Mutação Puntual , Compostos Radiofarmacêuticos , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Estudos de Coortes , Feminino , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias , Tomografia por Emissão de Pósitrons/métodos , Curva ROC , Estudos Retrospectivos , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Epidermal growth factor receptor (EGFR) mutations identify a unique biological subtype of non-small cell lung cancer (NSCLC). Treatment outcomes for EGFR-mutant locally advanced NSCLC patients have not been well described. METHODS: We retrospectively examined outcomes after combined modality therapy including thoracic radiation therapy (RT) in 123 patients with locally advanced NSCLC and known EGFR mutation status. Outcomes were compared using Kaplan-Meier analysis, the log-rank test, and multivariate Cox regression models. RESULTS: All 123 patients underwent thoracic RT; 25% had tumors with EGFR mutations and 94% had stage III disease. Overall, 81% received chemotherapy concurrent with RT and 55% underwent surgical resection. With a median follow-up of 27.5 months, the overall survival (OS) rate was significantly higher in patients with EGFR-mutant tumors than in those with wild-type EGFR tumors (2-year estimate: 92.6% versus 69.0%; p = .04). The 2-year relapse-free survival and distant recurrence rates did not differ significantly by genotype. The 2-year locoregional recurrence rate (LRR) was significantly lower in EGFR-mutant than in wild-type EGFR patients (17.8% versus 41.7%; p = .005). EGFR-mutant genotype was associated with a lower risk for LRR on multivariate analysis, but not OS, after adjusting for surgery and other potential confounders. CONCLUSION: We observed that EGFR-mutant patients with locally advanced NSCLC treated with RT had lower rates of LRR than wild-type EGFR patients, raising the hypothesis that EGFR mutations may confer sensitivity to RT and/or chemotherapy. The association between mutation status and OS after combined modality therapy was less robust. Our data may serve as a useful baseline estimate of outcomes by EGFR genotype for future prospective studies.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Terapia Combinada , Determinação de Ponto Final , Receptores ErbB/antagonistas & inibidores , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/radioterapia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Mutação , Estadiamento de Neoplasias , Modelos de Riscos Proporcionais , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do TratamentoRESUMO
PURPOSE: To assess the accuracy of maximum-intensity volumes (MIV) for fast contouring of lung tumors including respiratory motion. METHODS AND MATERIALS: Four-dimensional computed tomography (4DCT) data of 10 patients were acquired. Maximum-intensity volumes were constructed by assigning the maximum Hounsfield unit in all CT volumes per geometric voxel to a new, synthetic volume. Gross tumor volumes (GTVs) were contoured on all CT volumes, and their union was constructed. The GTV with all its respiratory motion was contoured on the MIV as well. Union GTVs and GTVs including motion were compared visually. Furthermore, planning target volumes (PTVs) were constructed for the union of GTVs and the GTV on MIV. These PTVs were compared by centroid position, volume, geometric extent, and surface distance. RESULTS: Visual comparison of GTVs demonstrated failure of the MIV technique for 5 of 10 patients. For adequate GTV(MIV)s, differences between PTVs were <1.0 mm in centroid position, 5% in volume, +/-5 mm in geometric extent, and +/-0.5 +/- 2.0 mm in surface distance. These values represent the uncertainties for successful MIV contouring. CONCLUSION: Maximum-intensity volumes are a good first estimate for target volume definition including respiratory motion. However, it seems mandatory to validate each individual MIV by overlaying it on a movie loop displaying the 4DCT data and editing it for possible inadequate coverage of GTVs on additional 4DCT motion states.
Assuntos
Imageamento Tridimensional/métodos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/radioterapia , Movimento , Interpretação de Imagem Radiográfica Assistida por Computador/métodos , Planejamento da Radioterapia Assistida por Computador/métodos , Tomografia Computadorizada por Raios X/métodos , Artefatos , Humanos , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
PURPOSE: Water equivalent path length (WEL) variations due to respiration can change the range of a charged particle beam and result in beam overshoot to critical organs or beam undershoot to tumor. We have studied range fluctuations by analyzing four-dimensional computed tomography data and quantitatively assessing potential beam overshoot. METHODS AND MATERIALS: The maximal intensity volume is calculated by combining the gross tumor volume contours at each respiratory phase in the four-dimensional computed tomography study. The first target volume calculates the maximal intensity volume for the entire respiratory cycle (internal target volume [ITV]-radiotherapy [RT]), and the second target volume is the maximal intensity volume corresponding to gated RT (gated-RT, approximately 30% phase window around exhalation). A compensator at each respiratory phase is calculated. Two "composite" compensators for ITV-RT and gated-RT are then designed by selecting the minimal compensator depth at the respective respiratory phase. These compensators are then applied to the four-dimensional computed tomography data to estimate beam penetration. Analysis metrics include range fluctuation and overshoot volume, both as a function of gantry angle. We compared WEL fluctuations observed in treating the ITV-RT versus gated-RT in 11 lung patients. RESULTS: The WEL fluctuations were <21.8 mm-WEL and 9.5 mm-WEL for ITV-RT and gated-RT, respectively for all patients. Gated-RT reduced the beam overshoot volume by approximately a factor of four compared with ITV-RT. Such range fluctuations can affect the efficacy of treatment and result in an excessive dose to a distal critical organ. CONCLUSION: Time varying range fluctuation analysis provides information useful for determining appropriate patient-specific treatment parameters in charged particle RT. This analysis can also be useful for optimizing planning and delivery.
Assuntos
Neoplasias Pulmonares/radioterapia , Movimento , Radioterapia Conformacional/métodos , Respiração , Tomografia Computadorizada por Raios X/métodos , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Grandes/patologia , Carcinoma de Células Grandes/radioterapia , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Expiração , Feminino , Humanos , Pulmão , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Planejamento da Radioterapia Assistida por Computador/métodos , Radioterapia Conformacional/instrumentação , Carga TumoralRESUMO
PURPOSE: We determined whether evaluation of treatment response is feasible by measuring metabolic tumor volume parameters on 18F-FDG (Fluorodeoxyglucose) PET-CT (Positron emission tomography-Computed tomography). We compared the response evaluation based on metabolic tumor volume parameters to a histopathologic and clinical response evaluation (clinical response criteria: RECIST criteria=Response evaluation criteria in solid tumors, and WHO criteria=World health organization). PATIENTS AND METHODS: A total of 51 study subjects with adenocarcinomas (Type I due to Siewert classification) of the esophagus underwent PET-CT scans before and after neoadjuvant chemoradiotherapy. Tumor volume, maximum and mean standardized uptake values (SUV) were assessed before and after chemoradiotherapy. Furthermore, the total lesion glycolysis (TLG) was calculated by multiplying the tumor volume by the mean SUV of the volume. Clinical response evaluation was performed with endoscopic ultrasound and CT using RECIST and WHO criteria. The reference standard for treatment response was the postsurgical histopathology. RESULTS: The decrease of tumor volume between the pre- and post-treatment PET-CT scans was a better predictor of histopathologic response and survival than the decrease of the SUV and of the clinical response evaluation based on RECIST and WHO criteria. The highest accuracy, however, was achieved when using the TLG for the identification of treatment responders. A decrease of the TLG by > 78% between pre- and post-therapy scans predicted histopathologic response with a sensitivity and specificity of 91% and 93%, respectively. CONCLUSIONS: Tumor volume and TLG can be used to assess treatment response and survival in patients with esophageal adenocarcinoma.
Assuntos
Adenocarcinoma/patologia , Adenocarcinoma/terapia , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/terapia , Adenocarcinoma/diagnóstico , Idoso , Terapia Combinada , Neoplasias Esofágicas/diagnóstico , Feminino , Fluordesoxiglucose F18 , Humanos , Masculino , Terapia Neoadjuvante , Tomografia por Emissão de Pósitrons , Tomografia Computadorizada por Raios X , Carga TumoralRESUMO
Cardiotoxicity is a known consequence of thoracic irradiation and there are multiple overlapping risk factors for cardiac disease and thoracic malignancies. In this study, we quantified the impact of thoracic (chemo)radiation on cardiac troponin T (TnT), creatine kinase-myocardial band (CK-MB) and aminoterminal pro-brain natriuretic peptide (NT-proBNP). Thirty patients receiving radiation therapy to the thorax with or without concurrent chemotherapy were evaluated. Serum was collected at baseline, 2 weeks into treatment and at the completion of radiation therapy. TnT, CK-MB and NT-proBNP were quantified using commercially available immunoassays. Cardiac dosimetric parameters and clinical risk factors were examined. In 29 of 30 patients, serum TnT remained undetectable (<0.01ng/mL) throughout (chemo)radiation. In the one patient with detectable serum TnT, levels did not change significantly with treatment. Similarly, thoracic (chemo)radiation did not cause statistically significant elevations in serum CK-MB and NT-proBNP. Thus, contemporary thoracic (chemo)radiation does not commonly result in elevations of serum TnT, CK-MB or NT-proBNP. Elevations in these markers during treatment merit further evaluation.
Assuntos
Biomarcadores/sangue , Creatina Quinase Forma MB/sangue , Neoplasias Esofágicas/terapia , Neoplasias Pulmonares/terapia , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Neoplasias do Timo/terapia , Troponina T/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Carcinoma Pulmonar de Células não Pequenas/terapia , Terapia Combinada , Neoplasias Esofágicas/sangue , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/radioterapia , Feminino , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/radioterapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Fatores de Risco , Carcinoma de Pequenas Células do Pulmão/sangue , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/radioterapia , Carcinoma de Pequenas Células do Pulmão/terapia , Neoplasias do Timo/sangue , Neoplasias do Timo/tratamento farmacológico , Neoplasias do Timo/radioterapiaRESUMO
PURPOSE: To report the feasibility of conducting a randomized study to compare the toxicity and efficacy of stereotactic body radiation therapy (SBRT) versus stereotactic body proton therapy (SBPT) for high-risk, medically inoperable, early-stage non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with medically inoperable NSCLC with high-risk features (centrally located or <5 cm T3 tumor or isolated lung parenchymal recurrences) were randomly assigned to SBRT or SBPT. Radiation dose was 50 Gy(relative biological effectiveness [RBE]) in 4 12.5-Gy(RBE) fractions prescribed to the planning target volume. Stereotactic body radiation therapy was given using 3-dimensional conformal radiation therapy or intensity modulated radiation therapy, and SBPT was given using passive scattering. Consistency in patient setup was ensured with on-board cone beam computed tomography for the SBRT group and with orthogonal X rays for the SBPT group. RESULTS: The study closed early owing to poor accrual, largely because of insurance coverage and lack of volumetric imaging in the SBPT group. Ultimately, 21 patients were enrolled, and 19 patients who received 50 Gy in 4 fractions were included for analysis (9 SBRT, 10 SBPT). At a median follow-up time of 32 months, median overall survival time was 28 months in the SBRT group and not reached in the SBPT group. Three-year overall survival was 27.8% and 90%, 3-year local control was 87.5% (8 of 9) and 90.0% (9 of 10), and 3-year regional control was 47.6% (5 of 9) and 90% (9 of 10) in the SBRT and SBPT groups, respectively. One patient in the SBPT group developed grade 3 skin fibrosis. No patients experienced grade 4/5 toxicity. CONCLUSION: Poor accrual, due to lack of volumetric imaging and insurance coverage for proton therapy, led to early closure of the trial and precluded accurate assessment of efficacy and toxicity. Comparable maturity of 2 radiation therapy modalities, particularly on-board imaging, and better insurance coverage for SBPT should be considered for future studies.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/radioterapia , Terapia com Prótons , Radiocirurgia , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Estudos de Viabilidade , Feminino , Humanos , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , RiscoRESUMO
PURPOSE: To quantitatively describe mediastinal and hilar lymph node movement in patients with lymph node-positive lung cancer. METHODS AND MATERIALS: Twenty-four patients with lung cancer who underwent four-dimensional computed tomography scanning at Massachusetts General Hospital were included in the study. The maximum extent of superior motion of the superior border was measured, as well as the maximum inferior movement of the inferior border. The average of these two values is defined as the peak-to-peak movement. This process was repeated for mediolateral (ML) and anterior-posterior (AP) movement. Linear regression was used to determine lymph node characteristics associated with peak-to-peak movement. Various uniform expansions were investigated to determine the expansion margins necessary to ensure complete internal target volume (ITV) coverage. RESULTS: The mean peak-to-peak displacements of paratracheal lymph nodes were 4 mm (craniocaudal [CC]), 2 mm (ML), and 2 mm (AP). For subcarinal lymph nodes, the mean peak-to-peak movements were 6 mm (CC), 4 mm (ML), and 2 mm (AP). The mean peak-to-peak displacements of hilar lymph nodes were 7 mm (CC), 1 mm (ML), and 4 mm (AP). On multivariate analysis, lymph node station and lymph node size were significantly related to peak-to-peak movement. Expansions of 8 mm for paratracheal nodes and 13 mm for subcarinal and hilar nodes would have been necessary to cover the ITV of 95% of these nodal masses. CONCLUSIONS: Subcarinal and hilar lymph nodes may move substantially throughout the respiratory cycle. In the absence of patient-specific information on nodal motion, expansions of at least 8 mm, 13 mm, and 13 mm should be considered to cover the ITV of paratracheal, subcarinal, and hilar lymph nodes, respectively.
Assuntos
Neoplasias Pulmonares/diagnóstico por imagem , Linfonodos/diagnóstico por imagem , Movimento , Respiração , Tomografia Computadorizada por Raios X/métodos , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Feminino , Humanos , Neoplasias Pulmonares/radioterapia , Metástase Linfática/diagnóstico por imagem , Masculino , Mediastino/diagnóstico por imagem , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
PURPOSE: The aim of this phase I/II study was to assess the long-term clinical benefits and toxicities of proton beam therapy for medically inoperable early-stage non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: From June 2006 to September 2011, 35 patients with medically inoperable T1N0M0 (central or superior location, 12 patients) or T2-3N0M0 (any location, 23 patients) NSCLC were treated with 87.5Gy at 2.5Gy/fraction of proton therapy. Toxicities were scored according to the Common Terminology Criteria for Adverse Events, version 4.0. RESULTS: The median follow-up time was 83.1months (95% CI: 69.2-97.1months). For all 35 patients, the 1, 3, and 5-year overall survival rates were 85.7%, 42.9%, and 28.1%, respectively. The 5-year local recurrence-free, regional recurrence-free, and distant metastasis-free survival rates were 85.0%, 89.2%, and 54.4%, respectively. Different T stages had no effect on local and regional recurrence (p=0.499, p=1.00). However, with the increase in T stages, the distant metastasis rate increased significantly (p=0.006). The most common adverse effects were dermatitis (grade 2, 51.4%; grade 3, 2.9%) and radiation pneumonitis (grade 2, 11.4%; grade 3, 2.9%). Other grade 2 toxicities included esophagitis (2.9%), rib fracture (2.9%), heart toxicities (5.7%), and chest wall pain (2.9%). CONCLUSIONS: According to our long-term follow-up data, proton therapy with ablative doses is well tolerated and effective in medically inoperable early-stage NSCLC. Systemic therapy should be considered to reduce the rate of distant metastasis in cases of T2 and T3 lesions.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/radioterapia , Neoplasias Pulmonares/radioterapia , Terapia com Prótons , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Estadiamento de Neoplasias , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Estudos Prospectivos , Terapia com Prótons/efeitos adversos , Dosagem Radioterapêutica , Taxa de SobrevidaRESUMO
PURPOSE: Phase I-II data regarding neoadjuvant cisplatin, 5-fluorouracil (5-FU), paclitaxel, and radiation (PFT-R) from our institution demonstrated encouraging pathologic complete response (pCR) rates. This article updates our experience with PFT-R, and compares these results to our experience with cisplatin, 5-FU, and radiation therapy (PF-R) in locally advanced esophageal cancer. PATIENTS AND METHODS: We searched the Massachusetts General Hospital cancer registry for esophageal cancer patients treated with radiation therapy and chemotherapy between 1994-2002. Records of patients treated with curative, neoadjuvant therapy were examined for chemotherapeutic regimen. Outcomes of patients treated with PF-R or PFT-R were assessed for response to therapy, toxicity, and survival. RESULTS: A total of 177 patients were treated with neoadjuvant therapy with curative intent; 164 (93%) received PF-R (n=81) or PFT-R (n=83). Median overall survival was 24 months. After a median follow-up of 54 months for surviving patients, 3-year overall survival was 40% with no significant difference between PF-R (39%) and PFT-R (42%). CONCLUSIONS: Our findings failed to demonstrate an improvement in pCR or survival with PFT-R vs. PF-R. These results do not support this regimen of concurrent neoadjuvant PFT-R in esophageal cancer, and suggest that further investigations into alternative regimens and novel agents are warranted.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/radioterapia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/mortalidade , Adenocarcinoma/radioterapia , Adenocarcinoma/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/radioterapia , Carcinoma de Células Escamosas/cirurgia , Cisplatino/administração & dosagem , Terapia Combinada/métodos , Esquema de Medicação , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/cirurgia , Feminino , Fluoruracila/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Estudos RetrospectivosRESUMO
PURPOSE: When using non-patient-specific treatment planning margins, respiratory motion may lead to geometric miss of the target while unnecessarily irradiating normal tissue. Imaging different respiratory states of a patient allows patient-specific target design. We used four-dimensional computed tomography (4DCT) to characterize tumor motion and create treatment volumes in 10 patients with lung cancer. These were compared with standard treatment volumes. METHODS AND MATERIALS: Four-dimensional CT and free breathing helical CT data of 10 patients were acquired. Gross target volumes (GTV) were delineated on the helical scan as well as on each phase of the 4D data. Composite GTVs were defined on 4DCT. Planning target volumes (PTV) including clinical target volume, internal margin (IM), and setup margin were generated. 4DPTVs with different IMs and standard PTVs were compared by computing centroid positions, volumes, volumetric overlap, and bounding boxes. RESULTS: Four-dimensional PTVs and conventional PTVs differed in volume and centroid positions. Overlap between 4DPTVs generated from two extreme tumor positions only compared with 10 respiratory phases was 93.7%. Comparing PTVs with margins of 15 mm (IM 5 mm) on composite 4D target volumes to PTVs with 20 mm (IM 10 mm) on helical CT data resulted in a decrease in target volume sizes by 23% on average. CONCLUSION: With patient-specific characterization of tumor motion, it should be possible to decrease internal margins. Patient-specific treatment volumes can be generated using extreme tumor positions on 4DCT. To date, more than 150 patients have been treated using 4D target design.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/radioterapia , Neoplasias Pulmonares/radioterapia , Movimento , Planejamento da Radioterapia Assistida por Computador/métodos , Respiração , Tomografia Computadorizada por Raios X/métodos , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Lesões por Radiação/prevenção & controleRESUMO
The purpose of this study is to accurately estimate the difference between the planned and the delivered dose due to respiratory motion and free breathing helical CT artefacts for lung IMRT treatments, and to estimate the impact of this difference on clinical outcome. Six patients with representative tumour motion, size and position were selected for this retrospective study. For each patient, we had acquired both a free breathing helical CT and a ten-phase 4D-CT scan. A commercial treatment planning system was used to create four IMRT plans for each patient. The first two plans were based on the GTV as contoured on the free breathing helical CT set, with a GTV to PTV expansion of 1.5 cm and 2.0 cm, respectively. The third plan was based on the ITV, a composite volume formed by the union of the CTV volumes contoured on free breathing helical CT, end-of-inhale (EOI) and end-of-exhale (EOE) 4D-CT. The fourth plan was based on GTV contoured on the EOE 4D-CT. The prescribed dose was 60 Gy for all four plans. Fluence maps and beam setup parameters of the IMRT plans were used by the Monte Carlo dose calculation engine MCSIM for absolute dose calculation on both the free breathing CT and 4D-CT data. CT deformable registration between the breathing phases was performed to estimate the motion trajectory for both the tumour and healthy tissue. Then, a composite dose distribution over the whole breathing cycle was calculated as a final estimate of the delivered dose. EUD values were computed on the basis of the composite dose for all four plans. For the patient with the largest motion effect, the difference in the EUD of CTV between the planed and the delivered doses was 33, 11, 1 and 0 Gy for the first, second, third and fourth plan, respectively. The number of breathing phases required for accurate dose prediction was also investigated. With the advent of 4D-CT, deformable registration and Monte Carlo simulations, it is feasible to perform an accurate calculation of the delivered dose, and compare our delivered dose with doses estimated using prior techniques.
Assuntos
Neoplasias Pulmonares/radioterapia , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador/métodos , Mecânica Respiratória , Tomografia Computadorizada por Raios X/métodos , Simulação por Computador , Humanos , Imageamento Tridimensional , Neoplasias Pulmonares/patologia , Método de Monte Carlo , Movimento/fisiologiaRESUMO
Radiation dose escalation has been shown to improve local control and survival in patients with non-small cell lung cancer in some studies, but randomized data have not supported this premise, possibly owing to adverse effects. Because of the physical characteristics of the Bragg peak, proton therapy (PT) delivers minimal exit dose distal to the target volume, resulting in better sparing of normal tissues in comparison to photon-based radiation therapy. This is particularly important for lung cancer given the proximity of the lung, heart, esophagus, major airways, large blood vessels, and spinal cord. However, PT is associated with more uncertainty because of the finite range of the proton beam and motion for thoracic cancers. PT is more costly than traditional photon therapy but may reduce side effects and toxicity-related hospitalization, which has its own associated cost. The cost of PT is decreasing over time because of reduced prices for the building, machine, maintenance, and overhead, as well as newer, shorter treatment programs. PT is improving rapidly as more research is performed particularly with the implementation of 4-dimensional computed tomography-based motion management and intensity modulated PT. Given these controversies, there is much debate in the oncology community about which patients with lung cancer benefit significantly from PT. The Particle Therapy Co-operative Group (PTCOG) Thoracic Subcommittee task group intends to address the issues of PT indications, advantages and limitations, cost-effectiveness, technology improvement, clinical trials, and future research directions. This consensus report can be used to guide clinical practice and indications for PT, insurance approval, and clinical or translational research directions.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/radioterapia , Consenso , Neoplasias Pulmonares/radioterapia , Terapia com Prótons/métodos , Carcinoma Pulmonar de Células não Pequenas/patologia , Ensaios Clínicos como Assunto , Humanos , Neoplasias Pulmonares/patologia , Movimento , Tratamentos com Preservação do Órgão , Órgãos em Risco/efeitos da radiação , Terapia com Prótons/economia , Lesões por Radiação/prevenção & controle , Planejamento da Radioterapia Assistida por Computador/métodos , Radioterapia de Intensidade Modulada/métodos , Espalhamento de Radiação , Carga TumoralAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Timoma/patologia , Neoplasias do Timo/patologia , Biópsia , Terapia Combinada , Diagnóstico Diferencial , Humanos , Masculino , Doenças do Mediastino/diagnóstico , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Timoma/tratamento farmacológico , Timoma/radioterapia , Timoma/cirurgia , Neoplasias do Timo/tratamento farmacológico , Neoplasias do Timo/radioterapia , Neoplasias do Timo/cirurgia , Tomografia Computadorizada por Raios XRESUMO
PURPOSE: To describe approaches to four-dimensional (4D) treatment planning, including acquisition of 4D-CT scans, target delineation of spatio-temporal image data sets, 4D dose calculations, and their analysis. METHODS AND MATERIALS: The study included patients with thoracic and hepatocellular tumors. Specialized tools were developed to facilitate visualization, segmentation, and analysis of 4D-CT data: maximum intensity volume to define the extent of lung tumor motion, a 4D browser to examine and dynamically assess the 4D data sets, dose calculations, including respiratory motion, and deformable registration to combine the dose distributions at different points. RESULTS: Four-dimensional CT was used to visualize and quantitatively assess respiratory target motion. The gross target volume contours derived from light breathing scans showed significant differences compared with those extracted from 4D-CT. Evaluation of deformable registration using difference images of original and deformed anatomic maps suggested the algorithm is functionally useful. Thus, calculation of effective dose distributions, including respiratory motion, was implemented. CONCLUSION: Tools and methods to use 4D-CT data for treatment planning in the presence of respiratory motion have been developed and applied to several case studies. The process of 4D-CT-based treatment planning has been implemented, and technical barriers for its routine use have been identified.
Assuntos
Interpretação de Imagem Assistida por Computador/métodos , Neoplasias Hepáticas/radioterapia , Neoplasias Pulmonares/radioterapia , Planejamento da Radioterapia Assistida por Computador/métodos , Respiração , Algoritmos , Estudos de Viabilidade , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Pulmonares/diagnóstico por imagem , Movimento , Tomografia por Emissão de Pósitrons , Intensificação de Imagem Radiográfica , Dosagem Radioterapêutica , Tomografia Computadorizada por Raios XRESUMO
PURPOSE: To determine the maximum-tolerated dose of docetaxel (DOC) in combination with carboplatin (CAR) and thoracic radiotherapy (RT), in the setting of trimodality treatment of patients with stage III non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: Thirty-two patients with biopsy-proven stage IIIA (n = 20) or IIIB (n = 12) NSCLC were given two initial cycles of CAR (area under the curve = 6) and DOC (75 mg/m(2)), subsequent RT (54 Gy) with concurrent weekly CAR (area under the curve = 2), and DOC at six dose levels from 10 to 40 mg/m(2), then surgery if the patient's disease was resectable. RESULTS: Three patients did not complete induction computed tomography (CT). Twenty-nine patients received concurrent CT/RT. Fifteen patients were eligible for surgery. Dose-limiting toxicities occurred in 2 patients, at dose levels two (atrial fibrillation) and three (transaminitis). The maximum-tolerated dose, as defined by the protocol, was not reached, although grade 3 and 4 toxicities were encountered at all dose levels. The most common more than or equal to grades 3 toxicities were neutropenia, nausea, vomiting, and fatigue. Four patients (13.3%) responded to induction CT. Ten patients (38.5%) responded to CT/RT. Eight surgical patients (57.1%) were downstaged, including 3 pathologic complete responses. Median relapse free and overall survivals are 8.5 and 12 months. One-year and estimated 2-year survival rates are 56.3 and 34.3%. CONCLUSION: This new regimen for stage III NSCLC of induction CAR/DOC, then weekly CAR/DOC with concurrent RT followed by surgery, can be safely administered and offers encouraging results. DOC at 30 mg/m(2) in combination with CAR and RT is recommended for Phase II study.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/terapia , Neoplasias Pulmonares/terapia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Terapia Combinada , Docetaxel , Relação Dose-Resposta a Droga , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/cirurgia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Indução de Remissão , Taxoides/administração & dosagem , Resultado do TratamentoRESUMO
BACKGROUND: We determined the impact of genetic alterations in EGFR, ALK, or KRAS on survival after radiotherapy for brain metastases in non-small cell lung cancer (NSCLC). METHODS: Of 172 genotyped NSCLC patients treated with radiotherapy for brain metastases in 2005-2012, 54 had cancers with EGFR mutations, 12 had ALK rearrangements, 38 had KRAS mutations, and 68 were wild-type (WT). Overall survival (OS) was determined. RESULTS: Median follow-up was 8.6 months. Median OS was 13.6 months for patients with EGFR mutations and 26.3 months for patients with ALK rearrangements, in contrast to 5.7 months for KRAS-mutant patients and 5.5 months for WT patients (P = .001). On multivariate analysis, adjusting for receipt of targeted therapy after cranial radiotherapy, ALK rearrangements were associated with improved OS (HR, 0.31; 95% CI, 0.13-0.74; P = .008). EGFR mutations were not significantly associated with improved OS on multivariate analysis (HR, 0.71; 95% CI, 0.37-1.38; P = .3). KRAS mutations were also not associated with improved OS (HR, 0.93; 95% CI, 0.59-1.47; P = .8). Receipt of targeted therapy after cranial radiotherapy was independently associated with improved OS (HR, 0.30; 95% CI, 0.17-0.54; P < .001). Receipt of chemotherapy after cranial radiotherapy, number of brain metastases, extracranial metastases, age, and performance status were also associated with OS. CONCLUSIONS: NSCLC patients with genetic alterations in ALK have improved survival outcomes after radiotherapy for brain metastases compared with EGFR, KRAS, or WT. Subsequent receipt of targeted therapy was associated with additional improvement in OS.