Prognostic value of (18) F-fluoroazomycin arabinoside PET/CT in patients with advanced non-small-cell lung cancer.

This study evaluated the prognostic value of positron emission tomography/computed tomography (PET/CT) using (18) F-fluoroazomycin arabinoside (FAZA) in patients with advanced non-small-cell lung cancer (NSCLC) compared with (18) F-fluorodeoxyglucose (FDG). Thirty-eight patients with advanced NSCLC (stage III, 23 patients; stage IV, 15 patients) underwent FAZA and FDG PET/CT before treatment. The PET parameters (tumor-to-muscle ratio [T/M] at 1 and 2 h for FAZA, maximum standardized uptake value for FDG) in the primary lesion and lymph node (LN) metastasis and clinical parameters were compared concerning their effects on progression-free survival (PFS) and overall survival (OS). In our univariate analysis of all patients, clinical stage and FAZA T/M in LNs at 1 and 2 h were predictive of PFS (P = 0.021, 0.028, and 0.002, respectively). Multivariate analysis also indicated that clinical stage and FAZA T/M in LNs at 1 and 2 h were independent predictors of PFS. Subgroup analysis of chemoradiotherapy-treated stage III patients revealed that only FAZA T/M in LNs at 2 h was predictive of PFS (P = 0.025). The FDG PET/CT parameters were not predictive of PFS. No parameter was a significant predictor of OS. In patients with advanced NSCLC, FAZA uptake in LNs, but not in primary lesions, was predictive of treatment outcome. These results suggest the importance of characterization of LN metastases in advanced NSCLC patients.

Dual-Energy Computed Tomography-Based Iodine Concentration Estimation for Evaluating Choroidal Malignant Melanoma Response to Treatment: Optimization and Primary Validation.

Contrast-enhanced imaging for choroidal malignant melanoma (CMM) is mostly limited to detecting metastatic tumors, possibly due to difficulties in fixing the eye position. We aimed to (1) validate the appropriateness of estimating iodine concentration based on dual-energy computed tomography (DECT) for CMM and optimize the calculation parameters for estimation, and (2) perform a primary clinical validation by assessing the ability of this technique to show changes in CMM after charged-particle radiation therapy. The accuracy of the optimized estimate (eIC_optimized) was compared to an estimate obtained by commercial software (eIC_commercial) by determining the difference from the ground truth. Then, eIC_optimized, tumor volume, and CT values (80 kVp, 140 kVp, and synthesized 120 kVp) were measured at pre-treatment and 3 months and 1.5−2 years after treatment. The difference from the ground truth was significantly smaller in eIC_optimized than in eIC_commercial (p < 0.01). Tumor volume, CT values, and eIC_optimized all decreased significantly at 1.5−2 years after treatment, but only eIC_commercial showed a significant reduction at 3 months after treatment (p < 0.01). eIC_optimized can quantify contrast enhancement in primary CMM lesions and has high sensitivity for detecting the response to charged-particle radiation therapy, making it potentially useful for treatment monitoring.

Differentiation between non-small cell lung cancer and radiation pneumonitis after carbon-ion radiotherapy by 18F-FDG PET/CT texture analysis.

The differentiation of non-small cell lung cancer (NSCLC) and radiation pneumonitis (RP) is critically essential for selecting optimal clinical therapeutic strategies to manage post carbon-ion radiotherapy (CIRT) in patients with NSCLC. The aim of this study was to assess the ability of 18F-FDG PET/CT metabolic parameters and its textural image features to differentiate NSCLC from RP after CIRT to develop a differential diagnosis of malignancy and benign lesion. We retrospectively analyzed 18F-FDG PET/CT image data from 32 patients with histopathologically proven NSCLC who were scheduled to undergo CIRT and 31 patients diagnosed with RP after CIRT. The SUV parameters, metabolic tumor volume (MTV), total lesion glycolysis (TLG) as well as fifty-six texture parameters derived from seven matrices were determined using PETSTAT image-analysis software. Data were statistically compared between NSCLC and RP using Wilcoxon rank-sum tests. Diagnostic accuracy was assessed using receiver operating characteristics (ROC) curves. Several texture parameters significantly differed between NSCLC and RP (p < 0.05). The parameters that were high in areas under the ROC curves (AUC) were as follows: SUVmax, 0.64; GLRLM run percentage, 0.83 and NGTDM coarseness, 0.82. Diagnostic accuracy was improved using GLRLM run percentage or NGTDM coarseness compared with SUVmax (p < 0.01). The texture parameters of 18F-FDG uptake yielded excellent outcomes for differentiating NSCLC from radiation pneumonitis after CIRT, which outperformed SUV-based evaluation. In particular, GLRLM run percentage and NGTDM coarseness of 18F-FDG PET/CT images would be appropriate parameters that can offer high diagnostic accuracy.

Imaging of Hypoxic Tumor: Correlation between Diffusion-weighted MR Imaging and 18F-fluoroazomycin Arabinoside Positron Emission Tomography in Head and Neck Carcinoma.

We investigated the usefulness of diffusion-weighted imaging (DWI) for detecting changes in the structure of hypoxic cells by evaluating the correlation between 18F-fluoroazomycin arabinoside (FAZA) positron emission tomography activity and DWI parameters in head and neck carcinoma. The diffusion coefficient corresponding to the slow compartment of a two-compartment model had a significant positive correlation with FAZA activity (ρ = 0.58, P = 0.016), whereas the diffusional kurtosis from diffusion kurtosis imaging had a significant negative correlation (ρ = -0.62, P = 0.008), which suggests that those DWI parameters might be useful as indicators for changes in cell structure.

Scanned carbon-ion beam therapy throughput over the first 7 years at National Institute of Radiological Sciences.

INTRODUCTION: In the 7 years since our facility opened, we have treated >2000 patients with pencil-beam scanned carbon-ion beam therapy. METHODS: To summarize treatment workflow, we evaluated the following five metrics: i) total number of treated patients; ii) treatment planning time, not including contouring procedure; iii) quality assurance (QA) time (daily and patient-specific); iv) treatment room occupancy time, including patient setup, preparation time, and beam irradiation time; and v) daily treatment hours. These were derived from the oncology information system and patient handling system log files. RESULTS: The annual number of treated patients reached 594, 7 years from the facility startup, using two treatment rooms. Mean treatment planning time was 6.0 h (minimum: 3.4 h for prostate, maximum: 9.3 h for esophagus). Mean time devoted to daily QA and patient-specific QA were 22 min and 13.5 min per port, respectively, for the irradiation beam system. Room occupancy time was 14.5 min without gating for the first year, improving to 9.2 min (8.2 min without gating and 12.8 min with gating) in the second. At full capacity, the system ran for 7.5 h per day. CONCLUSIONS: We are now capable of treating approximately 600 patients per year in two treatment rooms. Accounting for the staff working time, this performance appears reasonable compared to the other facilities.

Effects of image reconstruction algorithm on neurotransmission PET studies in humans: comparison between filtered backprojection and ordered subsets expectation maximization.

OBJECTIVES: Both reconstruction algorithms, filtered backprojection (FBP) and ordered subsets expectation maximization (OSEM), are widely used in clinical positron emission tomography (PET) studies. Image reconstruction for most neurotransmission PET scan data is performed by FBP, while image reconstruction for whole-body [18F]FDG scan data is usually performed by OSEM. Although several investigators have compared FBP and OSEM in terms of the quantification of regional radioactivity and physiological parameters calculated from PET data, only a few studies have compared the two reconstruction algorithms in PET studies that estimate neurotransmission, i.e., neuroreceptor and neurotransporter binding. In this study we compared mean regional radioactivity concentration in the late phase and binding potential (BP) between FBP and OSEM algorithms in neurotransmission PET studies for [11C]raclopride and [11C]DASB. METHODS: Dynamic PET scans with [11C]raclopride in 3-dimensional mode were performed on seven healthy subjects. Dynamic PET scans with [11C]DASB in 2-dimensional mode were performed on another seven subjects. OSEM images were post-filtered so that its transverse spatial resolution became similar to that of FBP with the same Hanning filter (Kernel FWHM 6 mm). In both PET studies we calculated the BP of [11C]raclopride and [11C]DASB by a reference tissue model for each ROI (region of interest). RESULTS: There was no significant difference in mean regional radioactivity concentration between FBP and OSEM for [11C]raclopride and [11C]DASB. Only +2.4 - +3.2%, but still a significant difference in BP of [11C]raclopride between FBP and OSEM was observed in the striatum. There was no significant difference in BP between FBP and OSEM in other than the striatum for [11C]raclopride and in all regions for [11C]DASB. In addition, there was no significant difference in root mean square error between FBP and OSEM when BP was calculated. CONCLUSIONS: The BP values were similar between FBP and OSEM algorithms with [11C]raclopride and [11C]DASB. This study indicates that OSEM can be used for human neurotransmission PET studies for calculating BP although OSEM was not necessarily superior to FBP in the present study.

Prognostic value of PET/CT with (18)F-fluoroazomycin arabinoside for patients with head and neck squamous cell carcinomas receiving chemoradiotherapy.

OBJECTIVE: The prognostic value of positron emission tomography/computed tomography (PET/CT) with (18)F-fluoroazomycin arabinoside (FAZA) was evaluated in patients with head and neck squamous cell carcinoma (HNSCC) who underwent chemoradiotherapy (CRT). METHODS: Twenty-nine patients with head and neck cancer underwent FAZA PET/CT before treatment. Data acquisition started 2 h after FAZA administration. In 26 patients with squamous cell carcinoma, FAZA uptakes by the primary lesions (tumor-muscle ratio in primary lesion: Pr T/M) and by the lymph node metastases (tumor-muscle ratio in lymph node metastasis) were compared with various clinical parameters. For the HNSCC patients who completed CRT protocol (n = 23), those who experienced disease progression were compared with those who did not experience disease progression with respect to the clinical and PET parameters. The prognostic values of the clinical and PET parameters were then evaluated with regard to progression-free survival (PFS). RESULTS: Pr T/M positively correlated with the lesion's maximum diameter, and it was significantly higher in stage IV lesions compared with stage I-III lesions. No significant differences were observed between the patients who experienced disease progression and those who did not, with respect to the clinical parameters. The average Pr T/M tended to be higher in patients with disease progression, although the differences were not statistically significant (p = 0.086). Kaplan-Meier analysis with log-rank tests indicated that Pr T/M was an only significant predictor of PFS among PET and clinical parameters evaluated (p = 0.010). CONCLUSIONS: FAZA uptake by the primary lesion was a significant prognostic indicator in HNSCC patients undergoing CRT. Hence, FAZA PET/CT may provide useful information in the management of HNSCC patients treated with CRT. Registration number of clinical trial's registry: UMIN000003440.

Carbon-Ion Pencil Beam Scanning Treatment With Gated Markerless Tumor Tracking: An Analysis of Positional Accuracy.

PURPOSE: Having implemented amplitude-based respiratory gating for scanned carbon-ion beam therapy, we sought to evaluate its effect on positional accuracy and throughput. METHODS AND MATERIALS: A total of 10 patients with tumors of the lung and liver participated in the first clinical trials at our center. Treatment planning was conducted with 4-dimensional computed tomography (4DCT) under free-breathing conditions. The planning target volume (PTV) was calculated by adding a 2- to 3-mm setup margin outside the clinical target volume (CTV) within the gating window. The treatment beam was on when the CTV was within the PTV. Tumor position was detected in real time with a markerless tumor tracking system using paired x-ray fluoroscopic imaging units. RESULTS: The patient setup error (mean ± SD) was 1.1 ± 1.2 mm/0.6 ± 0.4°. The mean internal gating accuracy (95% confidence interval [CI]) was 0.5 mm. If external gating had been applied to this treatment, the mean gating accuracy (95% CI) would have been 4.1 mm. The fluoroscopic radiation doses (mean ± SD) were 23.7 ± 21.8 mGy per beam and less than 487.5 mGy total throughout the treatment course. The setup, preparation, and irradiation times (mean ± SD) were 8.9 ± 8.2 min, 9.5 ± 4.6 min, and 4.0 ± 2.4 min, respectively. The treatment room occupation time was 36.7 ± 67.5 min. CONCLUSIONS: Internal gating had a much higher accuracy than external gating. By the addition of a setup margin of 2 to 3 mm, internal gating positional error was less than 2.2 mm at 95% CI.

Correction method for the physical dose calculated using Clarkson integration at the center of the spread-out Bragg peak for asymmetric field in carbon-ion radiotherapy.

PURPOSE: We previously proposed a calculation method using Clarkson integration to obtain the physical dose at the center of the spread-out Bragg peak (SOBP) for a treatment beam, the measurement point of which agrees with the isocenter [Tajiri et al. Med. Phys. 2013; 40: 071733-1-5]. However, at the measurement point which does not agree with the isocenter, the physical dose calculated by this method might have a large error. For this error, we propose a correction method. MATERIALS AND METHODS: To confirm whether the error can be corrected using in-air off axis ratio (OAR), we measured the physical dose at the center of an asymmetric square field and a symmetric square field and in-air OAR. For beams of which the measurement point does not agree with the isocenter, as applied to prostate cancer patients, the physical dose calculated using Clarkson integration was corrected with in-air OAR. RESULTS: The maximum difference between the physical dose measured at the center of an asymmetric square field and the product of in-air OAR and the physical dose at the center of a symmetric square field was - 0.12%. For beams as applied to prostate cancer patients, the differences between the measured physical doses and the physical doses corrected using in-air OAR were -0.17 ± 0.23%. CONCLUSIONS: The physical dose at the measurement point which does not agree with the isocenter, can be obtained from in-air OAR at the isocenter plane and the physical dose at the center of the SOBP on the beam axis.

Accuracy of methionine-PET in predicting the efficacy of heavy-particle therapy on primary adenoid cystic carcinomas of the head and neck.

BACKGROUND: We evaluated whether or not PET or PET/CT using L-methyl-[11C]-methionine (MET) can allow for the early prediction of local recurrence and metastasis, as well as the prognosis (disease-specific survival), in patients with adenoid cystic carcinoma of the head and neck treated by carbon ion beam radiotherapy. METHODS: This was a retrospective cohort study of sixty-seven patients who underwent a MET-PET or PET/CT study prior to and one month after the completion of carbon ion radiotherapy (CIRT). The minimum follow-up period for survivors was 12 months. The MET accumulation of the tumor was evaluated using the semiquantitative tumor to normal tissue ratio (TNR). A univariate analysis was conducted using the log-rank method, and the Cox model was used in a multivariate survival regression analysis. RESULTS: The average TNR prior to and following treatment was 4.8 (±1.5) and 3.0 (±1.3), respectively, showing a significant decrease following treatment. In the univariate analysis, a high TNR prior to treatment (TNRpre) was a significant factor for predicting the occurrence of metastasis and the disease-specific survival. A high TNR following treatment (TNRpost) was a significant factor for predicting the development of local recurrence. The residual ratio of TNR changes (TNRratio) seemed to be less useful than the TNRpre. In the multivariate analysis, the TNRpost and tumor size were the factors found to significantly influence the risk of local recurrence. The TNRpre, TNRratio and tumor size were all significant factors influencing the occurrence of metastasis. Regarding the disease-specific survival, the TNRpre and age were the only factors with a significant influence on the outcome. CONCLUSIONS: The TNRpre was a factor that was significantly related to the occurrence of metastasis and the disease-specific survival after CIRT for adenoid cystic carcinoma of the head and neck. The TNRpost was a factor that was significantly related to the development of local recurrence. Thus, MET-PET or PET/CT can be useful for predicting or determining the therapeutic efficacy of CIRT.

Calculation method using Clarkson integration for the physical dose at the center of the spread-out Bragg peak in carbon-ion radiotherapy.

PURPOSE: In broad-beam carbon-ion radiotherapy performed using the heavy-ion medical accelerator in Chiba, the number of monitor units is determined by measuring the physical dose at the center of the spread-out Bragg peak (SOBP) for the treatment beam. The total measurement time increases as the number of treatment beams increases, which hinders the treatment of an increased number of patients. Hence, Kusano et al. [Jpn. J. Med. Phys. 23(Suppl. 2), 65-68 (2003)] proposed a method to calculate the physical dose at the center of the SOBP for a treatment beam. Based on a recent study, the authors here propose a more accurate calculation method. METHODS: The authors measured the physical dose at the center of the SOBP while varying the circular field size and range-shifter thickness. The authors obtained the physical dose at the center of the SOBP for an irregularly shaped beam using Clarkson integration based on these measurements. RESULTS: The difference between the calculated and measured physical doses at the center of the SOBP varied with a change in the central angle of the sector segment. The differences between the calculated and measured physical doses at the center of the SOBP were within ± 1% for all irregularly shaped beams that were used to validate the calculation method. CONCLUSIONS: The accuracy of the proposed method depends on both the number of angular intervals used for Clarkson integration and the fineness of the basic data used for calculations: sampling numbers for the field size and thickness of the range shifter. If those parameters are properly chosen, the authors can obtain a calculated monitor unit number with high accuracy sufficient for clinical applications.

Predictive value of 3'-deoxy-3'-[18F]fluorothymidine positron emission tomography/computed tomography for outcome of carbon ion radiotherapy in patients with head and neck mucosal malignant melanoma.

OBJECTIVE: The purpose of this prospective study was to assess the prognostic value of 3'-deoxy-3'-[(18)F]fluorothymidine (FLT) positron emission tomography/computed tomography (PET/CT) for the outcome of carbon ion radiotherapy (CIRT) in patients with mucosal malignant melanoma (MMM) of the head and neck. METHODS: Thirteen patients (69 ± 13 years) with histologically proven MMM tumor were enrolled. CIRT was performed with a total dose of 57.6-64.0 gray equivalents per 16 fractions over a period of 4 weeks. FLT-PET/CT was performed before and again 1 month after CIRT. Tumor FLT uptake was quantitatively assessed using the maximum standardized uptake value (SUV(max)). FLT-PET parameters [pre-CIRT SUV(max), post-CIRT SUV(max), and the reduction rate (RR)] and clinical parameters [age, gender, tumor site, tumor status, gross tumor volume (GTV), and regional lymph node involvement] were evaluated in relation to survival estimates. The follow-up period was 16.1 ± 5.9 months for 9 deceased patients, and 36.7 ± 7.9 months for 4 survivors. RESULTS: Pre-CIRT SUV(max) of ≥4.3, age of ≥80 years old, sinonasal cavity tumor site, and GTV of ≥39 mL were found to be statistically significant prognostic factors for better overall survival. Pre-CIRT SUV(max) of ≥5.0, age of ≥80 years old, sinonasal cavity tumor site, and the absence of regional lymph node involvement were statistically significant prognostic factors for better metastasis-free survival. RR of ≥35 % and GTV of <73 mL were predictive of better local control. CONCLUSIONS: The present study indicated for the first time that in patients with the head and neck MMM, FLT-PET/CT imaging was useful for predicting the therapeutic outcome of CIRT. Our results will contribute to the establishment of an effective staging system for MMM based on prognostic factors, depending on treatment choice.

First clinical experience in carbon ion scanning beam therapy: retrospective analysis of patient positional accuracy.

Our institute has constructed a new treatment facility for carbon ion scanning beam therapy. The first clinical trials were successfully completed at the end of November 2011. To evaluate patient setup accuracy, positional errors between the reference Computed Tomography (CT) scan and final patient setup images were calculated using 2D-3D registration software. Eleven patients with tumors of the head and neck, prostate and pelvis receiving carbon ion scanning beam treatment participated. The patient setup process takes orthogonal X-ray flat panel detector (FPD) images and the therapists adjust the patient table position in six degrees of freedom to register the reference position by manual or auto- (or both) registration functions. We calculated residual positional errors with the 2D-3D auto-registration function using the final patient setup orthogonal FPD images and treatment planning CT data. Residual error averaged over all patients in each fraction decreased from the initial to the last treatment fraction [1.09 mm/0.76° (averaged in the 1st and 2nd fractions) to 0.77 mm/0.61° (averaged in the 15th and 16th fractions)]. 2D-3D registration calculation time was 8.0 s on average throughout the treatment course. Residual errors in translation and rotation averaged over all patients as a function of date decreased with the passage of time (1.6 mm/1.2° in May 2011 to 0.4 mm/0.2° in December 2011). This retrospective residual positional error analysis shows that the accuracy of patient setup during the first clinical trials of carbon ion beam scanning therapy was good and improved with increasing therapist experience.

PET/CT with 3'-deoxy-3'-[18F]fluorothymidine for lung cancer patients receiving carbon-ion radiotherapy.

OBJECTIVE: The aim of this study was to investigate the clinical value of 3'-deoxy-3'-[F]fluorothymidine-positron emission tomography/computed tomography (FLT-PET/CT) for lung cancer patients receiving carbon-ion radiotherapy. METHODS: Twenty consecutive patients with lung cancer underwent FLT-PET/CT before and after carbon-ion radiotherapy. Fifty minutes after intravenous injection of approximately 300 MBq of FLT, PET/CT data were acquired. Maximal standardized uptake value of the tumor was measured, from which the reduction rate of tumor FLT uptake was calculated. After treatment, the patients were followed (17-42 months for survivors) for the development of recurrence and survival. RESULTS: Primary responses to carbon-ion radiotherapy were partial in 13 patients, stable disease in six patients, and nonevaluable in one patient. Although tumor FLT uptake significantly decreased after treatment (P < 0.001), the presence of radiation pneumonitis hampered its precise evaluation. During the follow-up period, nine patients developed recurrence, and seven patients died including two deaths from other causes. Pretreatment FLT uptake of patients who developed recurrence and who died of lung cancer were significantly higher than that of patients who did not (P = 0.008 and 0.007, respectively). Kaplan-Meier analysis using a cut-off value also supported the prognostic value of pre-carbon-ion radiotherapy FLT-PET/CT. CONCLUSION: This investigation suggests that FLT-PET/CT is feasible in evaluating lung cancer patients undergoing carbon-ion radiotherapy. The presence of radiation pneumonitis can influence tumor FLT uptake and needs special attention. Pre-carbon-ion radiotherapy FLT-PET/CT seems to have a prognostic value and may contribute to decision-making on the treatment strategy.

Role of glucose metabolism and cellularity for tumor malignancy evaluation using FDG-PET/CT and MRI.

OBJECTIVE: Standardized uptake value (SUV) is affected by many factors. In that respect, the brain reference index (BRI: regions of interest of tumor/regions of interest of cerebellum) is one of the quantitative approaches to eliminate the variety of factors that affect SUV. MRI pulse sequence findings can also provide information about tissue cellularity. This information is useful for evaluating the malignancy of lesions. We evaluated the role of glucose metabolism and cellularity for the diagnosis of pancreatic tumor malignancy. METHOD: We performed a radionuclide 2-(18)F-fluoro-2-deoxyglucose ((18)F-FDG) uptake analysis and a signal intensity analysis using MRI on 16 presurgery patients with either proven or suspected pancreatic cancer. The tumor glucose metabolism was evaluated with SUV and BRI in an FDG-PET study. Tumor cellularity was determined with the MRI factors, apparent diffusion coefficient (ADC), T2 value and tumor to nontumor ratio of proton density. We compared these results with the pathological findings. RESULTS: SUV (= 0.855), BRI ( =0.875), and ADC ( =0.830) showed a larger the area under the curve than T2 value (= 0.582) and tumor to nontumor ratio of proton density ( = 0.786) according to the receiver operating characteristics analysis, and we therefore considered that these three factors were better indexes for the diagnosis of tumor malignancy. SUV and BRI had a high specificity. In contrast, ADC had a high sensitivity. CONCLUSION: The glucose metabolism with PET/CT and cellularity with MRI are different indexes for the diagnosis of tumor malignancy. Both provide necessary information for making an accurate diagnosis. Using both types of information may therefore help in obtaining a highly accurate diagnosis.