Mylene T. Truong

Phase I/II trial evaluating the anti-vascular endothelial growth factor monoclonal antibody bevacizumab in combination with the HER-1/epidermal growth factor receptor tyrosine kinase inhibitor erlotinib for patients with recurrent non-small-cell lung cancer.

PURPOSE Bevacizumab (Avastin; Genentech, South San Francisco, CA) is a recombinant, humanized anti-vascular endothelial growth factor monoclonal antibody. Erlotinib HCl (Tarceva, OSI-774; OSI Pharmaceuticals, New York, NY) is a potent, reversible, highly selective and orally available HER-1/epidermal growth factor receptor tyrosine kinase inhibitor. Preclinical data in various xenograft models produced greater growth inhibition than with either agent alone. Additionally, both agents have demonstrated benefit in patients with previously treated non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS A phase I/II study in two centers examined erlotinib and bevacizumab (A+T) in patients with nonsquamous stage IIIB/IV NSCLC with > or = one prior chemotherapy. In phase I, erlotinib 150 mg/day orally plus bevacizumab 15 mg/kg intravenously every 21 days was established as the phase II dose, although no dose-limiting toxicities were observed. Phase II assessed the efficacy and tolerability of A+T at this dose. Pharmacokinetic parameters were evaluated. ResultsForty patients were enrolled and treated in this study (34 patients at phase II dose); the median age was 59 years (range, 36 to 72 years), 21 were female, 30 had adenocarcinoma histology, nine were never-smokers, and 22 had > or = two prior regimens (three patients had > or = four prior regimens). The most common adverse events were mild to moderate rash, diarrhea, and proteinuria. Preliminary data showed no pharmacokinetic interaction between A + T. Eight patients (20.0%; 95% CI, 7.6% to 32.4%) had partial responses and 26 (65.0%; 95% CI, 50.2% to 79.8%) had stable disease as their best response. The median overall survival for the 34 patients treated at the phase II dose was 12.6 months, with progression-free survival of 6.2 months. CONCLUSION Encouraging antitumor activity and safety of A + T support further development of this combination for patients with advanced NSCLC and other solid tumors.

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.

Phase I Dose Escalation and Pharmacokinetic Study of Enzastaurin, an Oral Protein Kinase C Beta Inhibitor, in Patients With Advanced Cancer

PURPOSE This phase I study was conducted to determine the recommended dose of enzastaurin, an oral protein kinase C beta (PKCbeta) inhibitor, for phase II trials. Secondary objectives were maximum-tolerated dose (MTD), pharmacokinetics (PK), toxicity, and response. PATIENTS AND METHODS Patients at least 18 years of age with advanced cancer and an Eastern Cooperative Oncology Group performance status of 0 or 1 lower received enzastaurin orally once daily at a starting dose of 20 mg. Dose escalation proceeded using a modified Simon design. RESULTS All 47 patients enrolled (mean age, 58 years) received at least one dose of enzastaurin, with a median of two cycles (range, one to 17 cycles). Prevalent malignancies were lung (n = 10) and head and neck cancers (n = 9). Although no MTD was identified up to 700 mg/d, 525 mg was chosen as the recommended dose, and 12 additional patients were accrued at that level. Three dose-limiting toxicities (QTc changes) occurred: one at the 700-mg dose (patient discontinued), and two in the expansion cohort at the 525-mg dose. Total analytes (enzastaurin and its metabolites) exposure increased with increasing doses up to 240 mg, and appeared to plateau at 525 and 700 mg. Grade 1 chromaturia, fatigue, and other GI toxicities were the most common, while no clinically significant grade 3/4 toxicities occurred. Two deaths, unrelated to enzastaurin, occurred. Twenty-one patients (45%) achieved stable disease (SD) for two to 16 cycles. CONCLUSION On the basis of plasma exposures and safety data, enzastaurin 525 mg once daily is the recommended phase II dose. Enzastaurin is well tolerated up to 700 mg/d. Evidence of early activity was seen with significant stable disease.

Reversed Halo Sign in Invasive Pulmonary Fungal Infections

Computed tomography scans of documented pulmonary mold infections were reviewed for the presence of the reversed halo sign, a focus of ground-glass attenuation surrounded by a solid ring. The reversed halo sign was an early sign, seen in approximately 4% of patients with pulmonary mold infections, usually with zygomycosis.

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.

Detection of interval distant metastases: clinical utility of integrated CT-PET imaging in patients with esophageal carcinoma after neoadjuvant therapy.

The objective of the study was to determine the utility of integrated computed tomography / positron emission tomography (CT‐PET) imaging for detecting interval distant metastases and assessing therapeutic response in patients with locally advanced, potentially resectable esophageal carcinoma after neoadjuvant therapy.

Clinical utility of PET/CT in lymphoma

OBJECTIVE The purpose of this review is to assist interpreting radiologists in becoming familiar with the role of PET/CT in baseline staging and therapeutic response assessment in the management of lymphoma, in becoming aware of imaging pitfalls, and in understanding the natural behavior of lymphoma and the therapeutic options. CONCLUSION Therapeutic strategies for the management of lymphoma are constantly being refined to improve long-term survival with the lowest risk of toxicity to the patient. PET/CT is accurate for baseline staging and yields important prognostic information for determining the most appropriate initial treatment. Used for evaluation of treatment response, PET/CT can depict residual viable malignant lesions with greater accuracy than can other imaging techniques. The findings thereby influence decisions about the need for additional or alternative treatment.

Lipoid Pneumonia: Spectrum of Clinical and Radiologic Manifestations

OBJECTIVE Lipoid pneumonia results from accumulation of lipids in the alveoli and can be either exogenous or endogenous in cause based on the source of the lipid. Exogenous lipoid pneumonia is caused by inhalation or aspiration of animal fat or vegetable or mineral oil. Endogenous lipoid pneumonia is usually associated with bronchial obstruction. The purpose of this article is to review the pathogenesis and clinical and radiologic manifestations of exogenous and endogenous lipoid pneumonia. CONCLUSION The ability to recognize the radiologic manifestations of lipoid pneumonia is important because, in the appropriate clinical setting, these findings can be diagnostic.

Phase II study of a liposome-entrapped cisplatin analog (L-NDDP) administered intrapleurally and pathologic response rates in patients with malignant pleural mesothelioma

PURPOSE To determine pathologic response rates to liposome-entrapped cis-bisneodecanoato-trans-R,R-1,2-diaminocyclohexane platinum(II) (L-NDDP) administered intrapleurally in patients with malignant pleural mesothelioma. PATIENTS AND METHODS Thirty-three patients with malignant pleural mesothelioma and free-flowing pleural effusions received intrapleural L-NDDP once every 3 weeks at a dose of 450 mg/m2. Thoracoscopic evaluation with pleural biopsies was performed before therapy and then after every two cycles. The primary end point was pathologic response as determined by thoracoscopic biopsy. RESULTS After at least two cycles, post-treatment pleural biopsy analysis was negative in 14 patients for a pathologic response rate of 42% (95% CI, 25% to 61%). Median survival was 11.2 months. There were three treatment-related deaths secondary to peritonitis, cellulitis at the thoracoscopy site, and empyema. Grade 3 nonhematologic toxicities included infection, fever, dyspnea, and anorexia, which occurred in five (15%), one (3%), one (3%), and one (3%) patients, respectively. There were no grade 4 nonhematologic toxicities. Grade 3 or 4 neutropenia, thrombocytopenia, and anemia occurred in five (15%), three (9%), and two (6%) patients, respectively. Two patients with pathologic responses subsequently underwent pleural decortication. Both surgical specimens revealed residual tumor in regions that were not in direct communication with the pleural space. CONCLUSION Intrapleural L-NDDP therapy in this patient population is feasible with significant but manageable toxicity. Although pathologic responses are highly encouraging, areas of mesothelioma that are not in direct communication with the pleural space will evade drug exposure and limit efficacy in some patients. The optimal role of intrapleural L-NDDP therapy currently remains to be determined.

Preoperative Chemo-Radiation-Induced Ulceration in Patients with Esophageal Cancer: A Confounding Factor in Tumor Response Assessment in Integrated Computed Tomographic-Positron Emission Tomographic Imaging

Hypothesis: Positron emission tomography can be useful in predicting response of esophageal cancer after preoperative chemo-radiation therapy (CRT). We evaluated the use of integrated computed tomography (CT)-PET among patients with esophageal cancer being considered for resection after CRT. Methods: Three reviewers blinded to clinical and pathologic staging retrospectively reviewed the CT-PET scans of patients with esophageal cancer after preoperative CRT who underwent esophagectomy. [18F]-fluoro-2-deoxy-D-glucose uptake for residual malignancy was determined by visual analysis and semi-quantitatively when standardized uptake value (SUV) was ≥4. Results: Forty-two patients underwent esophageal resection. Using visual analysis, CT-PET had a sensitivity of 47% and specificity of 58% in detecting residual malignancy. Using semi-quantitative analysis, 19 patients had a SUV ≥4 in the region of the primary esophageal tumor and were interpreted as having residual malignancy (sensitivity 43%, specificity 50%). Of these 19, six had complete pathologic response to CRT. These false-positive results, due to therapy-induced ulceration detected at endoscopy, limit the use of CT-PET alone in detecting residual malignancy. Similarly, sensitivity (25%) and specificity (73%) of endoscopy/biopsy in detecting residual malignancy were poor. However, the accuracy of CT-PET in detecting residual malignancy was improved when combined with endoscopic findings. In the absence of ulceration at endoscopy, 8 of 8 patients with SUV ≥4 after chemo-radiation had residual malignancy at surgery. Conclusions: CRT-induced ulceration results in false-positive results on CT-PET and precludes accurate detection of residual esophageal tumor. However, CT-PET in combination with endoscopy is useful in identifying patients with a high risk of residual tumor post-CRT.