Xindong Sun

A randomized study of involved-field irradiation versus elective nodal irradiation in combination with concurrent chemotherapy for inoperable stage III nonsmall cell lung cancer.

Background:Radiation dose escalation is limited by the high incidence of pulmonary and esophageal toxicity, leading to calls for the omission of elective nodal irradiation (ENI) and the willingness to use involved-field irradiation (IFI) in patients with nonsmall cell lung cancer (NSCLC). Methods and Materials:A total of 200 eligible patients with inoperable stage III NSCLC were treated with concurrent chemoradiotherapy and randomized into either an IFI or ENI arm. A total of 4 to 6 cycles of cisplatin-based chemotherapy were delivered, and concurrent radiotherapy was started after the second cycle of chemotherapy. Three-dimensional conformal radiotherapy was delivered in once-daily fractions of 1.8 to 2 Gy to 68 to 74 Gy for IFI or 60 to 64 Gy for ENI. Results:Patients in the IFI arm achieved better overall response rate (90% vs. 79%, P = 0.032) and better 5-years local control rate (51% vs.36%, P = 0.032) than those in the ENI arm. The radiation pneumonitis rate in patients with IFI was lower than in patients with ENI (17% vs. 29%, P = 0.044), and similar trends appeared in the radiation esophagitis, myelosuppression, and radiation pericarditis between 2 study arms, although not significantly. The 1-, 2-, and 5-year survival rates were 60.4%, 25.6%, and 18.3% for the ENI arm and 69.9%, 39.4%, and 25.1% for the IFI arm, respectively. Only the 2-year survival rates were statistically significant (P = 0.048). Conclusion:IFI arm achieved better overall response and local control than ENI arm, and it allowed a dose of 68 to 74 Gy to be safely administered to patients with inoperable stage III NSCLC. Outcome improvement can be expected by conformal IFI combined with chemotherapy for stage III NSCLC.

Measuring Tumor Cell Proliferation with 18F-FLT PET During Radiotherapy of Esophageal Squamous Cell Carcinoma: A Pilot Clinical Study

The primary aim of this study was to use serial 18F-3′-deoxy-3′-fluorothymidine (FLT) PET/CT to measure tumor cell proliferation during radiotherapy of squamous cell carcinoma (SCC) of the esophagus. Methods: Twenty-one patients with inoperable locally advanced SCC of the esophagus underwent serial 18F-FLT PET/CT during radiotherapy. Each patient received a pretreatment scan, followed by 1–3 scans after delivery of 2, 6, 10, 20, 30, 40, 50, or 60 Gy to the tumor. Results: Among the 19 patients who completed radiotherapy without interruption, parameters reflecting 18F-FLT uptake in the tumor (i.e., maximum tumor standardized uptake value [SUVmax] and proliferation target volume) decreased steadily. All patients demonstrated an almost complete absence of proliferating esophageal tumor after 30 Gy and a complete absence after 40 Gy. In the 2 patients whose radiotherapy course was interrupted, 18F-FLT uptake in the tumor was greater after the interruption than before the interruption. Marked early reduction of 18F-FLT uptake in irradiated bone marrow was observed in all patients, even after only 2 Gy. All showed a complete absence of proliferating marrow in irradiated regions after 10 Gy. Both patients who underwent scans after completing the entire radiotherapy course showed no tumor uptake on 18F-FLT PET/CT but high uptake on 18F-FDG PET/CT. Pathologic examination of these regions revealed inflammatory infiltrates but no residual tumor. Conclusion: 18F-FLT uptake can be used to monitor the biologic response of esophageal SCC and normal tissue to radiotherapy. Increased uptake of 18F-FLT after treatment interruptions may reflect accelerated repopulation. 18F-FLT PET/CT may have an advantage over 18F-FDG PET/CT in differentiating inflammation from tumor.

Comparison of Tumor Volumes as Determined by Pathologic Examination and FDG-PET/CT Images of Non–Small-Cell Lung Cancer: A Pilot Study

PURPOSE To determine the cut-off standardized uptake value (SUV) on (18)F fluoro-2-deoxy-glucose (FDG) positron emission tomography/computed tomography (FDG-PET/CT) images that generates the best volumetric match to pathologic gross tumor volume (GTV(path)) for non-small-cell lung cancer (NSCLC). METHODS AND MATERIALS Fifteen patients with NSCLC who underwent FDG-PET/CT scans followed by lobectomy were enrolled. The surgical specimen was dissected into 5-7-mum sections at approximately 4-mm intervals and stained with hematoxylin and eosin. The tumor-containing area was outlined slice by slice and the GTV(path) determined by summing over all the slices, taking into account the interslice thickness and fixation-induced volume reduction. The gross tumor volume from the PET images, GTV(PET), was determined as a function of cut-off SUV. The optimal threshold or optimal absolute SUV was defined as the value at which the GTV(PET) was the same as the GTV(path). RESULTS The fixation process induced a volumetric reduction to 82% +/- 10% (range, 62-100%) of the original. The maximal SUV was 10.1 +/- 3.6 (range, 4.2-18.7). The optimal threshold and absolute SUV were 31% +/- 11% and 3.0 +/- 1.6, respectively. The optimal threshold was inversely correlated with GTV(path) and tumor diameter (p < 0.05), but the optimal absolute SUV had no significant correlation with GTV(path) or tumor diameter (p > 0.05). CONCLUSION This study evaluated the use of GTV(path) as a criterion for determining the optimal cut-off SUV for NSCLC target volume delineation. Confirmatory studies including more cases are being performed.

Molecular Imaging with 11C-PD153035 PET/CT Predicts Survival in Non–Small Cell Lung Cancer Treated with EGFR-TKI: A Pilot Study

Outcomes are suboptimal when molecularly targeted therapies are used in patient populations unselected for the molecular target. This pilot study examines the correlation of PET using 11C-labeled 4-N-(3-bromoanilino)-6,7-dimethoxyquinazoline (11C-PD153035), an imaging biomarker of epidermal growth factor receptor (EGFR), with outcomes in patients with non–small cell lung cancer (NSCLC) treated with the EGFR tyrosine kinase inhibitor erlotinib. Methods: Patients with advanced chemotherapy-refractory NSCLC were prospectively enrolled on a trial of erlotinib at a dose of 150 mg daily and imaged by 11C-PD153035 PET/CT at baseline, after 1–2 wk, and after 6 wk from the start of treatment. Overall survival and progression-free survival (OS and PFS, respectively) times were correlated with the 11C-PD153035 standardized uptake value (SUV) at each of the imaging times. Results: Twenty-one patients were enrolled. Follow-up to progression was complete in all patients and to death in 18 of 21. By Cox regression analysis, baseline maximum SUV correlated strongly with OS and PFS (hazard ratio = 0.40, P = 0.002, and hazard ratio = 0.044, P < 0.001, respectively) independent of histology. Patients with higher maximum SUV (≥median) survived more than twice as long as patients with lower maximum SUV (median OS = 11.4 vs. 4.6 mo, P = 0.002; PFS = 4.4 vs. 1.8 mo, P < 0.001). However, 11C-PD153035 uptake on follow-up scans was less well correlated with survival. Conclusion: Our preliminary results suggest 11C-PD153035 PET/CT may be a noninvasive and rapid method for identifying patients with refractory advanced NSCLC of adenocarcinoma or squamous histology likely to respond to the EGFR tyrosine kinase inhibitor but not for monitoring treatment response.

Serial hypoxia imaging with 99mTc-HL91 SPECT to predict radiotherapy response in nonsmall cell lung cancer.

Objective:To evaluate the relationship between 99mTc-HL91 (99mTc labeled 4,9-diaza-3,3,10,10-tetramethyldodecan-2,11-dione dioxime) SPECT (single photon emission computed tomography) hypoxia imaging and the treatment outcome and also to assess changes in tumor oxygenation during the course of radiotherapy. Methods:There were 32 patients enrolled in the study with pathologically proven nonsmall cell lung cancer that received 3-dimensional conformal radiotherapy. A 99mTc-HL91 SPECT scan was performed in all patients 1 or 2 days before radiotherapy and repeated during and after radiotherapy completion in 18 patients. The radioactivity ratios of tumor to normal tissue (T/N) were calculated. Results:The relationship between T/N ratios at 4 hours images after injection that was shown as the best of 3 acquired images before radiotherapy and tumor response and over survival were analyzed for all 32 patients. The results of 99mTc-HL91 imaging of 32 patients correlate well with tumor response (P = 0.002) and also patient survival (P = 0.043). The T/N ratios of 18 patients were decreased before, during and after radiotherapy and there was significant statistic difference (P = 0.000...). Conclusions:HL91 SPECT imaging identified the hypoxia status and changes during radiotherapy in lung cancer. It was confirmed that hypoxia imaging with HL91 SPECT before radiotherapy may predict tumor response and patient survival.

Raman study of lattice vibration modes and growth mechanism of KDP single crystals

The space group theoretical analyses and assignment of the lattice modes of the KDP crystal have been made, and the Raman spectra of their growth solution have been observed in different growth regions. The attention is focused on the analysis of the 912 cm -1 band arising from the H 2 PO 4 - anions in the interface between the KDP crystals and their growth solution. This has been assigned to the asymmetrical stretching mode of the deformation P(OH) 2 . From these results, the growth units of KDP crystal has been concluded to be the dimers of H 2 PO 4 anions. We consider that the result presented here is an important step towards the development of more complete crystal growth theories.

NONINVASIVE EVALUATION OF MICROSCOPIC TUMOR EXTENSIONS USING STANDARDIZED UPTAKE VALUE AND METABOLIC TUMOR VOLUME IN NON-SMALL-CELL LUNG CANCER

PURPOSE To prospectively evaluate whether maximal microscopic extensions (MEmax) correlate with maximal standardized uptake value (SUVmax) and metabolic tumor volume (MTV) at 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) images in non-small-cell lung cancer (NSCLC). METHODS AND MATERIALS Thirty-nine patients with Stage I-IIIA NSCLC underwent surgery after FDG-PET/CT scanning. SUVmax and MTV were calculated on the PET/CT images. The maximum linear distance from the tumor margin to the farthest extent of the tumor in every dimension was measured at the tumor section. The correlations among MEmax, SUVmax, MTV and other clinical pathologic parameters were analyzed. RESULTS MEmax for all patients had a significant correlation with SUVmax (r = 0.777, p = 0.008) and MTV (r = 0.724, p < 0.001). When expressed in terms of the probability of covering ME with respect to a given margin, we suggested that margins of 1.93 mm, 3.90 mm, and 9.60 mm for SUVmax ≤ 5, 5-10, and >10 added to the gross tumor volume would be adequate to cover 95% of ME. CONCLUSIONS This study demonstrated that tumors with high SUVmax and MTV have more MEmax and would therefore require more margin expansion from gross tumor volume to clinical target volume. FDG-PET/CT, especially for SUVmax, is promising and effective and merits additional study in noninvasive delimiting of the clinical target volume margin for NSCLC.

The prognostic value of 18F-fluorodeoxyglucose uptake by using serial positron emission tomography and computed tomography in patients with stage III nonsmall cell lung cancer.

Objectives:To determine the prognostic value of standardized uptake value (SUV) of 18F-fluorodeoxyglucose by serial positron emission tomography and computed tomography (PET/CT) in nonsmall cell lung cancer (NSCLC). Methods:Forty-seven patients (37 male, 10 female) with NSCLC in stage III were enrolled. All patients had at least 2 serial 18F-fluorodeoxyglucose PET/CT scans, both before and after therapy, and the maximum standardized uptake value (SUVmax) of the primary lung lesion was calculated. The value changes of SUVmax before and after treatment were calculated according to the following equation: &Dgr;SUV = (SUVbefore − SUVafter) × 100%/SUVbefore. Results:Of the 47 eligible patients, after a median follow-up of 23.5 months (range, 13–34 months), 26 patients had local and regional recurrence or metastasis and 21 remained disease-free. Significant differences in SUVmax were observed either before (P1 = 0.003) or after (P2 = 0.002) treatment between the 2 groups. However, the percent change of SUVmax before and after therapy were not significantly different (P = 0.054). Conclusions:SUV from 2 serial PET/CT scans, before and after concurrent chemoradiotherapy were significant predictors for local and regional recurrence or metastasis. SUV is a significant predictor for local and regional recurrence or metastasis in patients of NSCLC.

PET/CT imaging-guided dose painting in radiation therapy

Application of functional imaging to radiotherapy (RT) is a rapidly expanding field with the development of new modalities and techniques. Functional imaging of PET in conjunction with RT provides new avenues towards the clinical application of dose painting - a new RT strategy delivering optimized dose redistribution according to the functional imaging information to further improve tumour control. Two prototypical strategies of dose painting are reviewed: dose painting by contours (DPBC) and dose painting by numbers (DPBN). DPBN set a linear correlation of the boost dose and image intensity of this same voxel while homogeneous dose is given to the subvolume contoured by a threshold created in PET images in DPBC. Both comply with strict organs at risk (OAR) constraints and are alternatives for boosting subvolumes in clinical practice. This review focuses on the rationale, target validation, dose prescription verification and evaluation and recent clinical achievements in the field of integrating PET imaging into RT treatment planning. Further research is necessary in order to investigate unresolved problems in its routine clinical application thoroughly.

Lipiodol: a potential direct surrogate for cone-beam computed tomography image guidance in radiotherapy of liver tumor.

PURPOSE To investigate the feasibility of using lipiodol as a direct surrogate for target localization using cone-beam CT (CBCT) image guidance in radiotherapy (RT) of patients with unresectable liver tumors after transarterial chemoembolization. METHODS AND MATERIALS Forty-six patients with an unresectable solitary liver tumor were enrolled for RT using active breathing control (ABC) and CBCT image guidance after transarterial chemoembolization. Each patient had pre- and posttreatment CBCT in the first 10 fractions of treatment. Lipiodol retention was evaluated using daily CBCT scans, and volume of lipiodol retention in the liver was calculated and compared between planning CT and post-RT CT. Influence of lipiodol on dosimetry was evaluated by measuring doses using an ion chamber with and without the presence of lipiodol. Margin analysis was performed on the basis of both inter- and intrafractional target localization errors. RESULTS Twenty-eight patients successfully completed the study. The shape and size of lipiodol retention did not vary substantially during the course of treatment. The mean Dice similarity coefficient for the lipiodol volume in pretreatment CT and that in posttreatment CT was 0.836 (range, 0.817-0.885). The maximum change (ratio of the lipiodol volume in pretreatment CT to that in posttreatment CT) was 1.045. The mean dose changes with the presence of <10 mL lipiodol were -1.44% and 0.13% for 6 MV and 15 MV, respectively. With ABC and online CBCT image guidance, clinical target volume-planning target volume margins were determined to be 2.5 mm in the mediolateral direction, 2.9 mm in the anteroposterior direction, and 4.0 mm in the craniocaudal direction. CONCLUSIONS Lipiodol could be used as a direct surrogate for CBCT image guidance to improve the localization accuracy for RT of liver tumors. Combination of ABC and CBCT image guidance with lipiodol can potentially reduce the clinical target volume-planning target volume margin.