Gregory W. Gladish

Interobserver and Intraobserver Variability in Measurement of Non–Small-Cell Carcinoma Lung Lesions: Implications for Assessment of Tumor Response

PURPOSE Response of solid malignancies to therapy is usually determined by serial measurements of tumor size. The purpose of our study was to assess the consistency of measurements performed by readers evaluating lung tumors. MATERIALS AND METHODS The study group was composed of 33 patients with lung tumors more than 1.5 cm. Bidimensional (BD) and unidimensional (UD) measurements were performed on computed tomography (CT) scans according to the World Health Organization (WHO) criteria and the Response Evaluation Criteria in Solid Tumors (RECIST), respectively. Measurements were performed independently by five thoracic radiologists using printed film and were repeated after 5 to 7 days. Inter- and intraobserver measurement variations were estimated through statistical modeling. RESULTS There were 40 tumors with an average size of 1.8 to 8.0 cm (mean, 4.1 cm). Analysis of variance showed a significant difference (P <.05) among readers and among the measured nodules for UD and BD measurements. Interobserver misclassification rates were more than intraobserver misclassification rates using either progressive disease or response criteria. The probability of misclassifying a tumor with the WHO criteria or RECIST was greatest with interobserver measurements when criteria for progression (43% BD, 30% UD) were used and lowest with intraobserver measurements when criteria for response (2.5% BD, 3.0% UD) were used. In addition, interobserver misclassification rates were more than intraobserver misclassification rates for both regular and irregular tumors. CONCLUSION Measurements of lung tumor size on CT scans are often inconsistent and can lead to an incorrect interpretation of tumor response. Consistency can be improved if the same reader performs serial measurements for any one patient.

Attenuation correction of PET cardiac data with low-dose average CT in PET/CT

We proposed a low-dose average computer tomography (ACT) for attenuation correction (AC) of the PET cardiac data in PET/CT. The ACT was obtained from a cine CT scan of over one breath cycle per couch position while the patient was free breathing. We applied this technique on four patients who underwent tumor imaging with F18-FDG in PET/CT, whose PET data showed high uptake of F18-FDG in the heart and whose CT and PET data had misregistration. All four patients did not have known myocardiac infarction or ischemia. The patients were injected with 555-740MBq of F18-FDG and scanned 1h after injection. The helical CT (HCT) data were acquired in 16s for the coverage of 100cm. The PET acquisition was 3min per bed of 15cm. The duration of cine CT acquisition per 2cm was 5.9s. We used a fast gantry rotation cycle time of 0.5s to minimize motion induced reconstruction artifacts in the cine CT images, which were averaged to become the ACT images for AC of the PET data. The radiation dose was about 5mGy for 5.9s cine duration. The selection of 5.9s was based on our analysis of the respiratory signals of 600 patients; 87% of the patients had average breath cycles of less than 6s and 90% had standard deviations of less than 1s in the period of breath cycle. In all four patient studies, registrations between the CT and the PET data were improved. An increase of average uptake in the anterior and the lateral walls up to 48% and a decrease of average uptake in the septal and the inferior walls up to 16% with ACT were observed. We also compared ACT and conventional slow scan CT (SSCT) of 4s duration in one patient study and found ACT was better than SSCT in depicting average respiratory motion and the SSCT images showed motion-induced reconstruction artifacts. In conclusion, low-dose ACT improved registration of the CT and the PET data in the heart region in our study of four patients. ACT was superior than SSCT for depicting average respiration motion in a patient study.

Pulmonary artery sarcoma: a clinicopathologic and immunohistochemical study of 12 cases.

We report 12 cases of pulmonary artery sarcoma. The mean age at diagnosis was 48.4 years. Based on histomorphologic features and immunohistochemical findings, 2 tumors were classified as rhabdomyosarcoma, 4 as leiomyosarcoma, 1 as osteogenic sarcoma, 1 as angiosarcoma, and 4 as high-grade sarcoma. All patients underwent surgery. In addition, 7 patients received neoadjuvant or adjuvant therapy. Five patients died 3 to 23 months after surgery. Three patients were still alive at 8, 27, and 68 months at last follow-up. Another 3 patients were alive at 2, 15, and 40 months and then lost to follow-up. The 2 patients with the longest survival (40 months and 68 months) had a diagnosis of leiomyosarcoma. Both patients with rhabdomyosarcoma died at 3 months after surgery. Pulmonary artery sarcoma is an uncommon entity with a poor prognosis. The role of early diagnosis, histologic classification, surgical treatment, and adjuvant therapy in patient outcome is discussed.

Imaging of non-small cell lung cancer of the superior sulcus: part 2: initial staging and assessment of resectability and therapeutic response.

Imaging plays a crucial role in the diagnosis and staging of superior sulcus tumors, assessment of their resectability, determination of the optimal approach to disease management, and evaluation of the response to therapy. Computed tomography (CT), magnetic resonance (MR) imaging, and positron emission tomography (PET)/CT contribute important and complementary information. Whereas CT is optimal for depicting bone erosion and for staging of intrathoracic disease, MR imaging is superior for evaluating tumor extension to the intervertebral neural foramina, the spinal cord, and the brachial plexus, primarily because of the higher contrast resolution and multiplanar capability available with MR imaging technology. Use of PET/CT enables the detection of unsuspected nodal and distant metastases. However, imaging has only limited usefulness for evaluating the response of a tumor to induction therapy and detecting local recurrence, and surgical biopsy often is necessary to verify the results of therapy.

Association of Coronary Artery Calcification and Mortality in the National Lung Screening Trial: A Comparison of Three Scoring Methods

PURPOSE To evaluate three coronary artery calcification (CAC) scoring methods to assess risk of coronary heart disease (CHD) death and all-cause mortality in National Lung Screening Trial (NLST) participants across levels of CAC scores. MATERIALS AND METHODS The NLST was approved by the institutional review board at each participating institution, and informed consent was obtained from all participants. Image review was HIPAA compliant. Five cardiothoracic radiologists evaluated 1575 low-dose computed tomographic (CT) scans from three groups: 210 CHD deaths, 315 deaths not from CHD, and 1050 participants who were alive at conclusion of the trial. Radiologists used three scoring methods: overall visual assessment, segmented vessel-specific scoring, and Agatston scoring. Weighted Cox proportional hazards models were fit to evaluate the association between scoring methods and outcomes. RESULTS In multivariate analysis of time to CHD death, Agatston scores of 1-100, 101-1000, and greater than 1000 (reference category 0) were associated with hazard ratios of 1.27 (95% confidence interval: 0.69, 2.53), 3.57 (95% confidence interval: 2.14, 7.48), and 6.63 (95% confidence interval: 3.57, 14.97), respectively; hazard ratios for summed segmented vessel-specific scores of 1-5, 6-11, and 12-30 (reference category 0) were 1.72 (95% confidence interval: 1.05, 3.34), 5.11 (95% confidence interval: 2.92, 10.94), and 6.10 (95% confidence interval: 3.19, 14.05), respectively; and hazard ratios for overall visual assessment of mild, moderate, or heavy (reference category none) were 2.09 (95% confidence interval: 1.30, 4.16), 3.86 (95% confidence interval: 2.02, 8.20), and 6.95 (95% confidence interval: 3.73, 15.67), respectively. CONCLUSION By using low-dose CT performed for lung cancer screening in older, heavy smokers, a simple visual assessment of CAC can be generated for risk assessment of CHD death and all-cause mortality, which is comparable to Agatston scoring and strongly associated with outcome.

Phase 1b Study of Motesanib, an Oral Angiogenesis Inhibitor, in Combination with Carboplatin/Paclitaxel and/or Panitumumab for the Treatment of Advanced Non–Small Cell Lung Cancer

Purpose: Motesanib is a small-molecule antagonist of vascular endothelial growth factor receptor 1, 2, and 3, platelet-derived growth factor receptor, and Kit. This phase 1b study assessed the safety, maximum tolerated dose (MTD), and pharmacokinetics, and explored the objective response of motesanib plus carboplatin/paclitaxel and/or the fully human anti–epidermal growth factor receptor monoclonal antibody panitumumab in advanced non–small cell lung cancer (NSCLC). Experimental Design: Patients with unresectable NSCLC received sequentially escalating doses of motesanib [50, 125 mg once daily; 75 mg twice daily] orally continuously plus carboplatin/paclitaxel (arm A; first line) or panitumumab (arm B; first and second line) once every 21-day cycle or 125 mg once daily plus carboplatin/paclitaxel and panitumumab (arm C; first line). Results: Forty-five patients received motesanib. Three dose-limiting toxicities occurred: grade 4 pulmonary embolism (n = 1; arm A, 50 mg once daily) and grade 3 deep vein thrombosis (n = 2; arm A, 125 mg once daily; arm C). The MTD was 125 mg once daily. Common motesanib-related adverse events were fatigue (60% of patients), diarrhea (53%), hypertension, (38%), anorexia (27%), and nausea (22%). Three cases of cholecystitis occurred but only in the 75-mg twice-daily schedule, which was subsequently discontinued. At 125 mg once daily, motesanib pharmacokinetics were not markedly changed with carboplatin/paclitaxel coadministration; however, exposure to paclitaxel was moderately increased. The objective response rates were 17%, 0%, and 17% in arms A, B, and C, respectively. Conclusions: Treatment with motesanib was tolerable when combined with carboplatin/paclitaxel and/or panitumumab, with little effect on motesanib pharmacokinetics at the 125-mg once daily dose level. This dose is being investigated in an ongoing phase 3 study in NSCLC. Clin Cancer Res; 16(1); 279–90

Tumor cavitation during therapy with antiangiogenesis agents in patients with lung cancer

Purpose: Treatment of lung cancer patients with antiangiogenesis agents is a new promising paradigm. Tumor cavitation is frequently noted in these patients, but the clinical significance of this finding has not been fully determined. Our purposes were to evaluate the frequency, imaging characteristics, and clinical outcome of patients receiving antiangiogenesis agents who develop tumor cavitation, and correlate these findings with therapy related adverse events, especially hemoptysis. Methods: Retrospective analysis of lung cancer patients treated with antiangiogenesis agents in MD Anderson Cancer Center between June 1998 and June 2005. Clinical data were retrieved from medical records, and chest imaging findings were documented. Results: One hundred and twenty-four patients were treated in 10 different trials. All patients had advanced lung cancer and failed previous chemotherapy. Seventeen patients developed tumor cavitation during the trial (14%; median time to event, 1.8 months; range, 0.7–6.2 months), 16 patients (13%) had preexisting cavitary tumors, and 91 (73%) did not develop cavitation. Cavity formation was more common with squamous cell histology (p = 0.04) but was not associated with hemoptysis (p = 0.12), tumor location (central versus peripheral), imaging characteristics, progression-free survival (p = 0.56), or overall survival (p = 0.33). Hemoptysis was noted in five patients (median time to event, 1.3 months; range, 0.8–2.9 months). One of five patients with hemoptysis was fatal in a cavitary squamous cell tumor. Additional adverse events were hypertension, rash, and proteinuria, none associated with cavitation. Conclusion: Development of tumor cavitation is not rare in lung cancer patients treated with antiangiogenesis agents, but the clinical implications are minimal in most cases.

Cardiac motion during deep-inspiration breath-hold: Implications for breast cancer radiotherapy

PURPOSE Many patients with left-sided breast cancer receive adjuvant radiotherapy during deep-inspiration breath hold (DIBH) to minimize radiation exposure to the heart. We measured the displacement of the left anterior descending artery (LAD) and heart owing to cardiac motion during DIBH, relative to the standard tangential fields for left breast cancer radiotherapy. METHODS AND MATERIALS A total of 20 patients who had undergone computed tomography-based coronary angiography with retrospective electrocardiographic gating were randomly selected for the present study. The patients underwent scanning during DIBH to control the influence of respiration on cardiac motion. Standard medial and lateral tangential fields were placed, and the LADs were contoured on the systolic- and diastolic-phase computed tomography data sets by the clinicians. Displacement of the LAD during cardiac contractions was calculated in three directions: toward the posterior edge of the treatment fields, left-right, and anteroposterior. Displacement of the entire heart was measured on the maximal and minimal intensity projection computed tomography images. RESULTS The mean displacement of the LAD from cardiac contraction without the influence of respiration for 20 patients was 2.3 mm (range, 0.7-3.8) toward the posterior edge of the treatment fields, 2.6 mm (range, 1.0-6.8) in the left-right direction, and 2.3 mm (range, 0.6-6.5) in the anteroposterior direction. At least 30% of the LAD volume was displaced >5 mm in any direction in 2 patients (10%), and <10% of the LAD volume was displaced >5 mm in 10 patients (50%). The extent of displacement of the heart periphery during cardiac motion was negligible near the treatment fields. CONCLUSIONS Displacement of the heart periphery near the treatment fields was negligible during DIBH; however, displacement of the LAD from cardiac contraction varied substantially between and within patients. We recommend maintaining ≥ 5 mm of distance between the LAD and the field edge for patients undergoing breast cancer radiotherapy during DIBH.

Imaging of non-small cell lung cancer of the superior sulcus: Part 1: Anatomy, Clinical Manifestations, and Management

Non-small cell carcinomas of the superior pulmonary sulcus represent 3% of all lung cancers and are associated in most cases with a poor clinical outcome. Multimodality therapy with irradiation, chemotherapy, and surgery offers the best possibility for long-term survival and cure in most cases. For patients with pulmonary sulcus tumors that are not surgically resectable, chemoradiotherapy may help prolong survival and provide long-term pain relief. To accurately determine tumor resectability and to help optimize the planning and delivery of therapy, radiologists need a detailed knowledge of the clinical and imaging manifestations of disease in the individual patient and an awareness of the therapeutic options available. Accurate three-dimensional imaging and image interpretation are essential for mapping of the primary tumor before irradiation or surgical resection. Familiarity with the complex anatomy of the superior pulmonary sulcus is particularly crucial for determining the local-regional extension of a tumor and the most appropriate surgical approach.

Large Decreases in Standardized Uptake Values After Definitive Radiation Are Associated with Better Survival of Patients with Locally Advanced Non–Small Cell Lung Cancer

We evaluated potential associations between maximum standardized uptake value (SUVmax) on 18F-FDG PET before and after radiation therapy (RT) and survival outcomes for patients with locally advanced non–small cell lung cancer. Methods: Patients with stage III non–small cell lung cancer (n = 49) who had undergone 18F-FDG PET at the M.D. Anderson Cancer Center both before and up to 3.5 mo after undergoing radiochemotherapy were studied; exclusion criteria were patients with a history of thoracic surgery, RT, or other cancer or those who had received a total radiation dose less than 60 Gy. We assessed associations between overall survival (OS) or disease-free survival (DFS) and post-RT SUVmax and the extent of decrease in SUVmax in the primary tumor (PT) and regional lymph nodes (LNs). SUVmax was assessed as a continuous variable by Cox proportional hazards regression analysis. Results: Univariate and multivariate analyses showed that having a high post-RT SUVmax (either PT or LNs) was associated with a higher risk of death (univariate analyses: hazard ratio [HR] for PT SUVmax, 1.27, P < 0.0001; HR for LN SUVmax, 1.32, P = 0.004) and disease recurrence (univariate analyses: HR for PT SUVmax, 1.16, P = 0.004; HR for LN SUVmax, 1.32, P = 0.001). Moreover, after definitive RT, the greater the decrease in SUVmax in the lesion that had the highest SUVmax at diagnosis, the longer the OS (HR, 0.06; P = 0.002), DFS (HR, 0.03; P = 0.001), local–regional control (HR, 0.04; P = 0.002), and distant metastasis-free survival (HR, 0.07; P = 0.028). Conclusion: The post-RT SUVmax in both the PT and the LNs was a predictor of survival—specifically, the higher the residual SUVmax after RT, the poorer the OS and DFS; and the greater the decrease in SUVmax in the lesion with the highest SUVmax at diagnosis, the longer the OS and DFS. This information should help to identify patients who are at high risk of recurrence and for whom additional treatments can be designed accordingly.