Search

Several studies reported a central role of the endothelin type A receptor (ETAR) in tumor progression leading to the formation of metastasis. Here, we investigated the in vitro and in vivo anti-tumor effects of the FDA-approved ETAR antagonist, Ambrisentan, which is currently used to treat patients with pulmonary arterial hypertension. In vitro, Ambrisentan inhibited both spontaneous and induced migration/invasion capacity of different tumor cells (COLO-357 metastatic pancreatic adenocarcinoma, OvCar3 ovarian carcinoma, MDA-MB-231 breast adenocarcinoma, and HL-60 promyelocytic leukemia). Whole transcriptome analysis using RNAseq indicated Ambrisentan's inhibitory effects on the whole transcriptome of resting and PAR2-activated COLO-357 cells, which tended to normalize to an unstimulated profile. Finally, in a pre-clinical murine model of metastatic breast cancer, treatment with Ambrisentan was effective in decreasing metastasis into the lungs and liver. Importantly, this was associated with a significant enhancement in animal survival. Taken together, our work suggests a new therapeutic application for Ambrisentan in the treatment of cancer metastasis.

Background: We aimed to compare overall survival after standard-dose versus high-dose conformal radiotherapy with concurrent chemotherapy and the addition of cetuximab to concurrent chemoradiation for patients with inoperable stage III non-small-cell lung cancer., Methods: In this open-label randomised, two-by-two factorial phase 3 study in 185 institutions in the USA and Canada, we enrolled patients (aged ≥ 18 years) with unresectable stage III non-small-cell lung cancer, a Zubrod performance status of 0-1, adequate pulmonary function, and no evidence of supraclavicular or contralateral hilar adenopathy. We randomly assigned (1:1:1:1) patients to receive either 60 Gy (standard dose), 74 Gy (high dose), 60 Gy plus cetuximab, or 74 Gy plus cetuximab. All patients also received concurrent chemotherapy with 45 mg/m(2) paclitaxel and carboplatin once a week (AUC 2); 2 weeks after chemoradiation, two cycles of consolidation chemotherapy separated by 3 weeks were given consisting of paclitaxel (200 mg/m(2)) and carboplatin (AUC 6). Randomisation was done with permuted block randomisation methods, stratified by radiotherapy technique, Zubrod performance status, use of PET during staging, and histology; treatment group assignments were not masked. Radiation dose was prescribed to the planning target volume and was given in 2 Gy daily fractions with either intensity-modulated radiation therapy or three-dimensional conformal radiation therapy. The use of four-dimensional CT and image-guided radiation therapy were encouraged but not necessary. For patients assigned to receive cetuximab, 400 mg/m(2) cetuximab was given on day 1 followed by weekly doses of 250 mg/m(2), and was continued through consolidation therapy. The primary endpoint was overall survival. All analyses were done by modified intention-to-treat. The study is registered with ClinicalTrials.gov, number NCT00533949., Findings: Between Nov 27, 2007, and Nov 22, 2011, 166 patients were randomly assigned to receive standard-dose chemoradiotherapy, 121 to high-dose chemoradiotherapy, 147 to standard-dose chemoradiotherapy and cetuximab, and 110 to high-dose chemoradiotherapy and cetuximab. Median follow-up for the radiotherapy comparison was 22.9 months (IQR 27.5-33.3). Median overall survival was 28.7 months (95% CI 24.1-36.9) for patients who received standard-dose radiotherapy and 20.3 months (17.7-25.0) for those who received high-dose radiotherapy (hazard ratio [HR] 1.38, 95% CI 1.09-1.76; p=0.004). Median follow-up for the cetuximab comparison was 21.3 months (IQR 23.5-29.8). Median overall survival in patients who received cetuximab was 25.0 months (95% CI 20.2-30.5) compared with 24.0 months (19.8-28.6) in those who did not (HR 1.07, 95% CI 0.84-1.35; p=0.29). Both the radiation-dose and cetuximab results crossed protocol-specified futility boundaries. We recorded no statistical differences in grade 3 or worse toxic effects between radiotherapy groups. By contrast, the use of cetuximab was associated with a higher rate of grade 3 or worse toxic effects (205 [86%] of 237 vs 160 [70%] of 228 patients; p<0.0001). There were more treatment-related deaths in the high-dose chemoradiotherapy and cetuximab groups (radiotherapy comparison: eight vs three patients; cetuximab comparison: ten vs five patients). There were no differences in severe pulmonary events between treatment groups. Severe oesophagitis was more common in patients who received high-dose chemoradiotherapy than in those who received standard-dose treatment (43 [21%] of 207 patients vs 16 [7%] of 217 patients; p<0.0001)., Interpretation: 74 Gy radiation given in 2 Gy fractions with concurrent chemotherapy was not better than 60 Gy plus concurrent chemotherapy for patients with stage III non-small-cell lung cancer, and might be potentially harmful. Addition of cetuximab to concurrent chemoradiation and consolidation treatment provided no benefit in overall survival for these patients., Funding: National Cancer Institute and Bristol-Myers Squibb., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Radiation Therapy Oncology Group (RTOG) 0515 is a Phase II prospective trial designed to quantify the impact of positron emission tomography (PET)/computed tomography (CT) compared with CT alone on radiation treatment plans (RTPs) and to determine the rate of elective nodal failure for PET/CT-derived volumes., Methods: Each enrolled patient underwent definitive radiation therapy for non-small-cell lung cancer (≥ 60 Gy) and had two RTP datasets generated: gross tumor volume (GTV) derived with CT alone and with PET/CT. Patients received treatment using the PET/CT-derived plan. The primary end point, the impact of PET/CT fusion on treatment plans was measured by differences of the following variables for each patient: GTV, number of involved nodes, nodal station, mean lung dose (MLD), volume of lung exceeding 20 Gy (V20), and mean esophageal dose (MED). Regional failure rate was a secondary end point. The nonparametric Wilcoxon matched-pairs signed-ranks test was used with Bonferroni adjustment for an overall significance level of 0.05., Results: RTOG 0515 accrued 52 patients, 47 of whom are evaluable. The follow-up time for all patients is 12.9 months (2.7-22.2). Tumor staging was as follows: II = 6%; IIIA = 40%; and IIIB = 54%. The GTV was statistically significantly smaller for PET/CT-derived volumes (98.7 vs. 86.2 mL; p < 0.0001). MLDs for PET/CT plans were slightly lower (19 vs. 17.8 Gy; p = 0.06). There was no significant difference in the number of involved nodes (2.1 vs. 2.4), V20 (32% vs. 30.8%), or MED (28.7 vs. 27.1 Gy). Nodal contours were altered by PET/CT for 51% of patients. One patient (2%) has developed an elective nodal failure., Conclusions: PET/CT-derived tumor volumes were smaller than those derived by CT alone. PET/CT changed nodal GTV contours in 51% of patients. The elective nodal failure rate for GTVs derived by PET/CT is quite low, supporting the RTOG standard of limiting the target volume to the primary tumor and involved nodes., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Currently there are no commercially available tools to generate composite plans across different treatment modalities and/or different planning image sets. Without a composite plan, it may be difficult to perform a meaningful dosimetric evaluation of the overall treatment course. In this paper, we introduce a method to generate composite biological effective dose (BED) plans over multiple radiotherapy treatment modalities and/or multistage plans, using deformable image registration. Two cases were used to demonstrate the method. Case I was prostate cancer treated with intensity-modulated radiation therapy (IMRT) and a permanent seed implant. Case II involved lung cancer treated with two treatment plans generated on two separate computed tomography image sets. Thin-plate spline or optical flow methods were used as appropriate to generate deformation matrices. The deformation matrices were then applied to the dose matrices and the resulting physical doses were converted to BED and added to yield the composite plan. Cell proliferation and sublethal repair were considered in the BED calculations. The difference in BED between normal tissues and tumor volumes was accounted for by using different BED models, alpha/beta values, and cell potential doubling times. The method to generate composite BED plans presented in this paper provides information not available with the traditional simple dose summation or physical dose summation. With the understanding of limitations and uncertainties of the algorithms involved, it may be valuable for the overall treatment plan evaluation., (2010 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.)

Purpose: To assess the radiation dosimetry and biodistribution of (99m)Tc-labeled ethylene dicysteine deoxyglucose ((99m)Tc-EC-DG) in patients with non-small-cell lung cancer (NSCLC)., Methods: Serial whole-body scans were acquired 0, 2, 4, 6 and 24 h after injection of (99m)Tc-EC-DG (925 MBq) in seven NSCLC patients. Radiation dosimetry, blood clearance and SPECT imaging of the primary tumor were assessed., Results: The critical organ was the bladder wall, with average radiation absorbed dose over all seven patients of 2.47x10(-2) mGy/MBq. The average effective dose equivalent and effective dose were 6.20x10(-3) mSv/MBq (6.89 mSv/1,110 MBq) and 5.90x10(-3) mSv/MBq (6.54 mSv/1,110 MBq), respectively. The primary tumor was visualized with SPECT in six patients. On final pathology, one patient had a granuloma, which did not enhance with (99m)Tc-EC-DG., Conclusion: (99m)Tc-EC-DG has acceptable dosimetric and biodistribution properties as a diagnostic tumor-imaging agent. Future studies are planned to evaluate its diagnostic potential.

A new stereotactic frame system was designed at Indiana University to utilize the precision motion control of newer accelerator couches and treat obese patients previously untreatable in other frame systems during stereotactic body radiation therapy (SBRT). The repositioning accuracy and target reproducibility of this frame was evaluated in the treatment of both lung and liver tumors. The external coordinate system on the new frame was validated using a phantom system. Translational motions were carried out using couch motors. Five patients were treated with SBRT and twenty-three verification CT scans were acquired. The displacement of the gross tumor volume (GTV) and adjacent vertebral body between the original CT scan and the verification CT scans was determined. The mean setup accuracy for the patient study was less than 5 mm. Mean displacement of the GTV was 3.0 mm (0.0-6.0 mm) in the lateral (x) direction, 4.1 mm (0.0-8.9 mm) in the superior-inferior (y) direction, and 2.6 mm (0.0-10.0 mm) in the cranio-caudal (z) direction. Comparison of vertebral body position showed mean displacement of 2.4 mm (0.0 to 8.0 mm), 1.9 mm (0.0 mm to 2.0 mm), and 0.9 mm (0.0 to 5.0 mm) for the same shift directions. Repositioning could be accurately carried out from an initial reference position using the treatment couch controllers. Adequate set-up accuracy using a frame system capable of accommodating wide girth patients was achieved and was comparable to other published studies for narrower frames. With these results, a 5 mm expansion for PTV margins remains the standard for our institution.

Purpose: To determine whether the standardized uptake value (SUV) of [(18)F]fluorodeoxyglucose uptake by positron emission tomography could be a prognostic factor for non-small-cell lung cancer (NSCLC)., Patients and Methods: One hundred sixty-two patients with stage I to IIIb NSCLC were analyzed. Overall survival (OS), disease-free survival (DFS), distant metastasis-free survival (DMFS), and local-regional control (LRC) were calculated by the Kaplan-Meier method and evaluated with the log-rank test. The prognostic significance was assessed by univariate and multivariate analyses., Results: There were 93 patients treated with surgery and 69 patients treated with radiotherapy. A cutoff of 5 for the SUV for the primary tumor showed the best discriminative value. The SUV for the primary tumor was a significant predictor of OS (P = .02) in both groups. Low SUVs ( 5.0; surgery group, P = .02; radiotherapy group, P = .0005). Low SUVs ( 5.0; stage I or II, P = .02; stage IIIa or IIIb, P = .004). However, using the same cutoff point of 5, the SUV for regional lymph nodes was not a significant indicator for DFS (P = .19), LRC (P = .97), or DMFS (P = .17). The multivariate analysis showed that the SUV for the primary tumor was a significant prognostic factor for OS (P = .03) and DFS (P = .001)., Conclusion: The SUV of the primary tumor was the strongest prognostic factor among the patients treated by curative surgery or radiotherapy.

Purpose: Demonstrate the path integration of a four-dimensional (4-D) dose distribution onto the 3-D anatomy., Materials and Methods: A computer-generated 4-D thoracic phantom with a lung tumour was constructed. Eight respiratory phases were generated. A radiotherapy treatment plan was applied to all the phases resulting in a 4-D dose distribution. An elastic image registration algorithm was used to find the vector displacement between all the image elements and the end expiration phase. The path-integrated tissue dose distribution and each component dose distribution were compared with the planned dose distribution., Results: Numerical path integration was performed to calculate the tissue dose distribution. Loss of tumour coverage was the predominant effect observed with tumour motion in this study. The loss was asymmetric and dependent on the tumour trajectory., Conclusion: The elastic image registration allowed an accurate path integration through a 4-D data set to produce an accurate 3-D tissue dose estimate.

Purpose: To analyze the relationship between lung motion and skin surface motion during respiration, determine the uncertainties and variability of such a relationship, and assess the potential of reducing internal target margin for gated radiotherapy., Methods and Materials: Three healthy volunteers and four lung cancer patients were recruited in a prospective imaging study using MRI to track the internal lung and external skin motion during breathing. The relationship between the lung and skin motion was modeled using linear regression analysis. The slope of the linear fit and its confidence interval were analyzed for different lung locations, skin surface locations, and breathing patterns from separate imaging sessions. The margins of the internal target volume were calculated based on the residual lung motion during gating and its uncertainties from multiple treatment fractions for the gated treatment., Results: The slope and confidence interval of the linear regression from the motion analysis were uniquely defined by the locations of the lung, skin surface, and breathing patterns. Statistically significant differences were observed among individuals and between different times of measurement. The normal free-breathing motion averaged from all volunteer and patient data was 13.4 +/- 7.4 mm along the superior-inferior (SI) direction and 6.9 +/- 2.6 mm along the anterior-posterior (AP) direction. With simulated respiratory gating, the average margin reduction was 5.5 +/- 4.8 mm and 1.6 +/- 1.0 mm, respectively, along the SI and AP directions (or 36% +/- 15% and 25% +/- 14%, respectively, relative to free-breathing motion)., Conclusion: Because respiratory movement is rather complex, the relationship between the lung and skin surface motion is affected by many anatomic and physiologic factors. The reduction of internal target margin and efficacy of the free-breathing gating technique should be assessed for individual cases.

Purpose: To measure the internal lung motion due to respiration using magnetic resonance images (MRIs); to evaluate the correlation between lung motion and skin surface motion and the reliability of tracking lung motion with external fiducials., Methods and Materials: An MRI protocol using fast gradient-echo sequences was developed to acquire dynamic cine images of the thoracoabdominal region along the axial, sagittal, and coronal planes. The subjects (3 healthy volunteers and 4 lung cancer patients) were instructed to perform normal or altered breathing during MRI. Lung vessels identified on MRI were used as anatomic landmarks for internal lung structures. From sagittal cine MRI scans, the positions of the lung vessels and skin surface were tracked and their movements measured. Correlation between the movements of the external markers and internal structures was then calculated and analyzed., Results: Lung vessel motion in the superior-inferior (SI) direction correlated best with mid-upper abdominal skin surface movement (correlation coefficient, 0.89 +/- 0.09 and 0.87 +/- 0.23 for volunteers and patients, respectively). The anterior-posterior (AP) vessel motion generally correlated poorly with the skin surface movement, with marker placement on the upper chest yielding the strongest results (correlation coefficient, 0.72 +/- 0.23 and 0.44 +/- 0.27 for volunteers and patients, respectively). The strength of the correlation depended on the locations of the tracked vessels, locations of the skin surface, and subjects' breathing patterns. The best correlation was seen between the motion of an abdominal fiducial and SI lung motion. Significant intersubject variability was also observed., Conclusion: Movement of an external fiducial may not correlate fully with, or predict, internal lung motion. Effective monitoring of respiration may have to rely on a combination of multiple fiducials and other physiologic parameters, such as lung volume and/or air flow.

The optimal treatment for intrathoracic tumors such as lung and esophageal cancer requires an improvement of therapeutic ratio to increase efficacy of the cancer-cell kill and decrease the normal-cell kill. This is not an easy task because sensitive normal cells such as alveoli and epithelial cells in the esophagus and bronchus surround these tumors. How to minimize the damage of such sensitive normal cells within irradiated fields without sparing cancer cells is a major issue for radiation oncologists, especially as concurrent chemoradiotherapy has become more standard treatment. One way to achieve this task is accurate delineation of the target volume, which will be emphasized here. Some other ways to achieve it are biological protection by ethyol, keratinocyte growth factors, biologically targeted treatments such as C225 and celecoxib, and anti-angiogenesis, which have been briefly addressed in Dr. Cox's article in this Journal. Molecular imaging is a new diagnostic and therapeutic modality that offers great potential for accuracy of target definition, although it is not quite ready for routine clinical use at the present time. Accurate target definition and contouring in cases of carcinoma of the lung and esophagus depend on expertise of diagnostic and therapeutic medical teams. There we review the normal anatomy, diagnostic methods, and tumor delineation of cancer of the lung and esophagus.

Purpose: To determine whether superior-inferior lung tumor motion is predictable by tumor size or location, or pulmonary function test results., Methods and Materials: Superior-inferior tumor motion was measured on orthogonal radiographs taken during simulation of 22 patients with inoperable lung cancer diagnosed by orthogonal radiographs., Results: The tumor size averaged 5.5 +/- 3.1 cm (range 1.5-12 cm). Seven of 11 central tumors demonstrated some motion compared with 5 of 11 peripheral tumors. Four of 5 upper lobe tumors moved compared with 8 of 17 tumors that were either middle or lower lobe lesions. The mean fourth rib motion was 7.3 +/- 3.2 mm (range 2-15). The mean FeV(1) was 1.8 +/- 1.2 (range 0.55-5.33. The mean diffusing capacity of the lung for carbon monoxide was 14.0 +/- 6.5 (range 7.8-21.9). The mean total lung capacity was 6.5 +/- 1.2 (range 3.3-8.4). None of these parameters correlated with tumor motion. Although lateral tumor motion could not be consistently determined, 1 tumor moved 10 mm anterior-posteriorly., Conclusions: Lung tumors often move significantly during respiration. Tumor motion is not predictable by tumor size or location, or pulmonary function test results. Therefore, tumor motion must be measured in all patients. Measurement in three dimensions will likely be necessary to maximize the irradiated lung volumes or choose beam arrangements parallel to the major axis of motion.