Takashi Terauchi

Phase I/II Study of Concurrent Chemoradiotherapy for Localized Nasal Natural Killer/T-Cell Lymphoma: Japan Clinical Oncology Group Study JCOG0211

PURPOSE To explore a more effective treatment for localized nasal natural killer (NK)/T-cell lymphoma, we conducted a phase I/II study of concurrent chemoradiotherapy. PATIENTS AND METHODS Treatments comprised concurrent radiotherapy (50 Gy) and 3 courses of dexamethasone, etoposide, ifosfamide, and carboplatin (DeVIC). Patients with a newly diagnosed stage IE or contiguous IIE disease with cervical node involvement and a performance status (PS) of 0 to 2 were eligible for enrollment. The primary end point of the phase II portion was a 2-year overall survival in patients treated with the recommended dose. RESULTS Of the 33 patients enrolled, 10 patients were enrolled in the phase I portion and a two thirds dose of DeVIC was established as the recommended dose. Twenty-seven patients (range, 21 to 68; median, 56 years) treated with the recommended dose showed the following clinical features: male:female, 17:10; stage IE, 18; stage IIE, 9; B symptoms present, 10; elevated serum lactate dehydrogenase, 5; and PS 2, 2. With a median follow-up of 32 months, the 2-year overall survival was 78% (95% CI, 57% to 89%). This compared favorably with the historical control of radiotherapy alone (45%). Of the 26 patients assessable for a response, 20 (77%) achieved a complete response, with one partial response. The overall response rate was 81%. The most common grade 3 nonhematologic toxicity was mucositis related to radiation (30%). No treatment-related deaths were observed. CONCLUSION Concurrent chemoradiotherapy using multidrug resistance-nonrelated agents and etoposide is a safe and effective treatment for localized nasal NK/T-cell lymphoma and warrants further investigation.

Neoadjuvant Chemotherapy in Breast Cancer: Prediction of Pathologic Response with PET/CT and Dynamic Contrast-enhanced MR Imaging—Prospective Assessment

PURPOSE To clarify whether fluorine 18 ((18)F) fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) and dynamic contrast-enhanced (DCE) magnetic resonance (MR) imaging performed after two cycles of neoadjuvant chemotherapy (NAC) can be used to predict pathologic response in breast cancer. MATERIALS AND METHODS Institutional human research committee approval and written informed consent were obtained. Accuracy after two cycles of NAC for predicting pathologic complete response (pCR) was examined in 142 women (mean age, 57 years: range, 43-72 years) with histologically proved breast cancer between December 2005 and February 2009. Quantitative PET/CT and DCE MR imaging were performed at baseline and after two cycles of NAC. Parameters of PET/CT and of blood flow and microvascular permeability at DCE MR were compared with pathologic response. Patients were also evaluated after NAC by using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 based on DCE MR measurements and European Organization for Research and Treatment of Cancer (EORTC) criteria and PET Response Criteria in Solid Tumors (PERCIST) 1.0 based on PET/CT measurements. Multiple logistic regression analyses were performed to examine continuous variables at PET/CT and DCE MR to predict pCR, and diagnostic accuracies were compared with the McNemar test. RESULTS Significant decrease from baseline of all parameters at PET/CT and DCE MR was observed after NAC. Therapeutic response was obtained in 24 patients (17%) with pCR and 118 (83%) without pCR. Sensitivity, specificity, and accuracy to predict pCR were 45.5%, 85.5%, and 82.4%, respectively, with RECIST and 70.4%, 95.7%, and 90.8%, respectively, with EORTC and PERCIST. Multiple logistic regression revealed three significant independent predictors of pCR: percentage maximum standardized uptake value (%SUV(max)) (odds ratio [OR], 1.22; 95% confidence interval [CI]: 1.11, 1.34; P < .0001), percentage rate constant (%k(ep)) (OR, 1.07; CI: 1.03, 1.12; P = .002), and percentage area under the time-intensity curve over 90 seconds (%AUC(90)) (OR, 1.04; CI: 1.01, 1.07; P = .048). When diagnostic accuracies are compared, PET/CT is superior to DCE MR for the prediction of pCR (%SUV(max) [90.1%] vs %κ(ep) [83.8%] or %AUC(90) [76.8%]; P < .05). CONCLUSION The sensitivities of %SUV(max) (66.7%), %k(ep) (51.7%), and %AUC(90) (50.0%) at (18)F-FDG PET/CT and DCE MR after two cycles of NAC are not acceptable, but the specificities (96.4%, 92.0%, and 95.2%, respectively) are high for stratification of pCR cases in breast cancer.

Glut-1 expression and enhanced glucose metabolism are associated with tumour grade in bone and soft tissue sarcomas: a prospective evaluation by [18F]fluorodeoxyglucose positron emission tomography

PurposeThis study was conducted to investigate whether 18F-fluorodeoxyglucose (FDG) uptake, quantified by positron emission tomography (PET), correlates with histological variables including tumour grade, cell proliferation, cell cycle control integrity and glucose metabolism in patients with bone and soft tissue sarcomas.MethodsEighty-two patients clinically suspected of having a bone or soft tissue sarcoma underwent FDG PET within 1 week prior to operation and 63 patients (mean age 48 years, range 18–74 years) were enrolled in the complete analysis. We excluded 17 patients with pathologically confirmed benign tumours and two patients with uncontrolled diabetes or concomitant malignancy from data analysis. Maximum and average standardised uptake values (SUVs) of the primary lesion were compared with histological variables including tumour differentiation, the presence of necrosis, MIB-1 score, mitotic score, p53 overexpression, MIB-1 grade, mitotic grade and GLUT-1 expression.ResultsSignificant correlations were found between maximal and mean SUVs and MIB-1 grade, mitotic grade, MIB-1 score, tumour differentiation and mitotic score. The mean and maximal SUVs were significantly higher in tumours with p53 overexpression than in those without p53 overexpression (p<0.0001). GLUT-1-positive tumours had significantly higher mean (6.5±4.2 vs 1.1±0.2, p=0.006) and maximal SUVs (8.8±5.4 vs 1.7±0.5, p=0.005) than the GLUT-1-negative tumours. GLUT-1 intensity correlated positively with both mean (r=0.500, p<0.0001) and maximal SUVs (r=0.509, p<0.0001). Mu ltiple linear regression analysis showed a significant correlation between maximal SUV and MIB-1 grade (p<0.0001).ConclusionThe enhanced glucose metabolism, as determined by SUV, is a strong index of tumour grade in bone and soft tissue sarcomas.

Multicenter Phase II Study of Bendamustine Plus Rituximab in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma

PURPOSE Effective and less aggressive therapies are required for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who are not eligible for or have undergone autologous stem-cell transplantation (ASCT). The present phase II study assessed the efficacy and safety of bendamustine plus rituximab (BR) in this population. PATIENTS AND METHODS Patients with relapsed or refractory DLBCL treated with one to three prior chemotherapy regimens received rituximab 375 mg/m(2) intravenous (IV) infusion on day 1 and bendamustine 120 mg/m(2) by IV infusion on days 2 and 3 of each 21-day cycle for up to six cycles. The primary end point was overall response rate (ORR), and the secondary end points were complete response (CR) rate, progression-free survival (PFS), and safety. RESULTS Sixty-three patients were enrolled, and 59 received BR. The median age was 67 years (range, 36 to 75 years), and 62.7% of patients were 65 years of age or older. Fifty-seven patients (96.6%) were previously treated with rituximab-containing chemotherapy. The ORR was 62.7% (95% CI, 49.1% to 75.0%), with a CR rate of 37.3% (95% CI, 25.0% to 50.9%). The ORRs were comparable between patients ≥ 65 years of age and less than 65 years (62.2% and 63.6%, respectively). The median PFS was 6.7 months (95% CI, 3.6 to 13.7 months). The most frequently observed grade 3 or 4 adverse events were hematologic: lymphopenia (78.0%), neutropenia (76.3%), leukopenia (72.9%), CD4 lymphopenia (66.1%), and thrombocytopenia (22.0%). CONCLUSION BR is a promising salvage regimen for patients with relapsed or refractory DLBCL after rituximab-containing chemotherapy, warranting further investigation.

Comparative study of FDG PET/CT and conventional imaging in the staging of rhabdomyosarcoma

ObjectiveThe current study was conducted to compare the diagnostic accuracy between 18F-fluoro-2-deoxy-d-glucose (FDG) positron emission tomography (PET)/computed tomography (CT), and conventional imaging (CI) for the staging and re-staging of patients with rhabdomyosarcomas.MethodsThirty-five patients who underwent FDG PET/CT prior to treatment were evaluated retrospectively. CI methods consisted of 99mTc-hydroxymethylene diphosphonate bone scintigraphy, chest radiograph, whole body CT, and magnetic resonance imaging of the primary site. The images were reviewed and two boardcertified radiologists reached a diagnostic consensus. Tumor stage was confirmed by histological examination and/or follow-up examinations.ResultsInterpretation on the basis of FDG PET/CT, and CI, diagnostic accuracies of the T and N stages were similar. Using FDG PET/CT, the M stage was correctly assigned in 31 patients (89%), whereas the accuracy of CI in M stage was 63%. TNM stage was correctly assessed with FDG PET/CT in 30 of 35 patients (86%) and with CI in 19 of 35 patients (54%). The overall TNM staging and M staging accuracies of FDG PET/CT were significantly higher than that of CI (P < 0.01).ConclusionsFDG PET/CT is more accurate than CI regarding clinical staging and re-staging of patients with rhabdomyosarcomas.

Japanese guideline for the oncology FDG-PET/CT data acquisition protocol: synopsis of Version 1.0.

This synopsis outlines the Japanese guideline Version 2.0 for the data acquisition protocol of oncology FDG-PET/CT scans that was created by a joint task force of the Japanese Society of Nuclear Medicine Technology, the Japanese Society of Nuclear Medicine and the Japanese Council of PET Imaging, and was published in Kakuigaku-Gijutsu 2013; 33:377–420 in Japanese. The guideline aims at standardizing the PET image quality among PET centers and different PET camera models by providing criteria for the IEC body phantom image quality as well as for the patient PET image quality based on the noise equivalent count (NEC), NEC density and liver signal-to-noise ratio, so that the appropriate scanning parameters can be determined for each PET camera. This Version 2.0 covers issues that were not focused on in Version 1.0, including the accuracy of the standardized uptake value (SUV), effect of body size together with adjustment of scanning duration, and time-of-flight (TOF) reconstruction technique. Version 2.0 also presents data acquired with new PET camera models that were not tested in Version 1.0. Reference values for physical indicators of phantom image quality have been updated as well.

A meta-analysis of 18F-Fluoride positron emission tomography for assessment of metastatic bone tumor

PurposeThe aim of this study was to assess the diagnostic performance of 18F-Fluoride positron emission tomography (PET) or positron emission tomography/computed tomography (PET/CT) compared with bone scintigraphy (BS) planar or BS planar and single photon emission computed tomography (SPECT) in evaluating patients with metastatic bone tumor.Materials and methodsWe performed a meta-analysis of all available studies addressing the diagnostic accuracy of 18F-Fluoride PET, 18F-Fluoride PET/CT, BS planar, and BS planar and SPECT for detecting the metastatic bone tumor. We determined sensitivities and specificities across studies, calculated positive and negative likelihood ratios, and drew summary receiver operating characteristic curves using hierarchical regression models. We also compared the effective dose and cost-effectiveness estimated by data from the enrolled studies between 18F-Fluoride PET or PET/CT and BS planar or BS planar and SPECT.ResultsWhen comparing all studies with data on 18F-Fluoride PET or PET/CT, sensitivity and specificity were 96.2% [95% confidence interval (CI) 93.5–98.9%] and 98.5% (95% CI 97.0–100%), respectively, on a patient basis and 96.9% (95% CI 95.9–98.0%) and 98.0% (95% CI 97.1–98.9%), respectively, on a lesion basis. The Az values of 18F-Fluoride PET or PET/CT were 0.986 for the patient basis and 0.905 for the lesion basis, whereas those of BS or BS and SPECT were 0.866 for the patient basis and 0.854 for the lesion basis. However, the estimated effective dose and average cost-effective ratio were poorer for 18F-Fluoride PET or PET/CT than those of BS planar or BS planar and SPECT.Conclusion18F-Fluoride PET or PET/CT has excellent diagnostic performance for the detection of metastatic bone tumor, but the estimated effective dose and average cost-effective ratio are at a disadvantage compared with BS planar or BS planar and SPECT.

A multicentre phase II study of vorinostat in patients with relapsed or refractory indolent B-cell non-Hodgkin lymphoma and mantle cell lymphoma.

Although initial rituximab‐containing chemotherapies achieve high response rates, indolent B‐cell non‐Hodgkin lymphoma (B‐NHL), such as follicular lymphoma (FL), is still incurable. Therefore, new effective agents with novel mechanisms are anticipated. In this multicentre phase II study, patients with relapsed/refractory indolent B‐NHL and mantle cell lymphoma (MCL) received vorinostat 200 mg twice daily for 14 consecutive days in a 21‐d cycle until disease progression or unacceptable toxicity occurred. The primary endpoint was overall response rate (ORR) in FL patients and safety and tolerability in all patients. Secondary endpoints included progression‐free survival (PFS). Fifty‐six eligible patients were enrolled; 50 patients (39 with FL, seven with other B‐NHL, and four with MCL) were evaluable for ORR, and 40 patients had received rituximab‐containing prior chemotherapeutic regimens. For the 39 patients with FL, the ORR was 49% [95% confidence interval (CI): 32·4, 65·2] and the median PFS was 20 months (95% CI: 11·2, 29·7). Major toxicities were manageable grade 3/4 thrombocytopenia and neutropenia. Vorinostat offers sustained antitumour activity in patients with relapsed or refractory FL with an acceptable safety profile. Further investigation of vorinostat for clinical efficacy is warranted.

Phase II/III Study of R-CHOP-21 Versus R-CHOP-14 for Untreated Indolent B-Cell Non-Hodgkin's Lymphoma: JCOG 0203 Trial

PURPOSE Rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is one of the most effective front-line therapies to treat indolent B-cell lymphoma. Granulocyte colony-stimulating factor (G-CSF), which potentiates antibody-dependent rituximab cytotoxicity, is used to shorten CHOP intervals. To improve progression-free survival (PFS) in patients treated with R-CHOP as the primary end point, we conducted a phase III study. PATIENTS AND METHODS Patients with untreated stages III to IV indolent B-cell lymphoma were randomly assigned to six cycles of R-CHOP every 3 weeks (R-CHOP-21) or every 2 weeks (R-CHOP-14) with G-CSF. Maintenance rituximab was not allowed. RESULTS Three hundred patients were enrolled. At the median follow-up time of 5.2 years, there was no significant difference in PFS between arms for the 299 eligible patients; the median was 3.7 (R-CHOP-21) v 4.7 (R-CHOP-14) years, 57% v 58% at 3 years, and 41% v 43% at 6 years, respectively (hazard ratio [HR], 0.92; 95% CI, 0.68 to 1.25; one-sided P = .30). The median overall survival (OS) time was not reached in either arm, and there was no significant difference (6-year OS: 87% [R-CHOP-21] v 88% [R-CHOP-14]; HR, 1.15; 95% CI, 0.57 to 2.30; one-sided P = .65). Although grade 4 neutropenia and grade 3 infections were more frequent in the R-CHOP-21 group, R-CHOP was feasible in both arms. CONCLUSION The R-CHOP dose-dense strategy failed to improve PFS of patients with untreated indolent B-cell lymphoma. Further improvement of first-line treatment or investigations on postremission therapy following R-CHOP should be explored.

Evaluation of 18F-2-deoxy-2-fluoro-glucose positron emission tomography for gastric cancer screening in asymptomatic individuals undergoing endoscopy

18F-2-deoxy-2-fluoro-glucose Positron Emission Tomography (FDG-PET) has been recently proposed as a promising cancer-screening test. However, the validity of FDG-PET in cancer screening has not been evaluated. We investigated the sensitivity of FDG-PET compared with upper gastric endoscopy in gastric cancer screening for asymptomatic individuals. A total of 2861 consecutive subjects (1600 men and 1261 women) who were asymptomatic and who underwent both FDG-PET and upper gastrointestinal endoscopy between 1 February 2004 and 31 January 2005 were included in this study. Both endoscopists and a radiologist were unaware of the results of the other diagnostic tests. The FDG-PET images were examined using criteria determined by the pattern of FDG accumulation. Sensitivity and specificity of FDG-PET were calculated compared with endoscopic diagnosis as the gold standard. Among 2861 subjects enrolled in the study, there were 20 subjects with gastric cancer, of whom 18 were T1 in depth of cancer invasion. Positive FDG-PET results were obtained only in 2 of the 20 cancer subjects. The calculated sensitivity and specificity for overall gastric cancers were 10.0% (95% confidence interval (CI): 1.2–31.7%) and 99.2% (95% CI: 98.8–99.5%), respectively. 18F-2-deoxy-2-fluoro-glucose Positron Emission Tomography was poorly sensitive for detection of gastric cancer in the early stages.