Keiichi Jingu

Prospective Comparison of Surgery Alone and Chemoradiotherapy With Selective Surgery in Resectable Squamous Cell Carcinoma of the Esophagus

PURPOSE Esophagectomy remains the mainstay treatment for esophageal cancer, although retrospective studies have suggested that chemoradiotherapy (CRT) is as effective as surgery. To determine whether CRT can substitute for surgery as the primary treatment modality, we performed a prospective direct comparison of outcomes after treatment in patients with resectable esophageal cancer who had received CRT and those who had undergone surgery. METHODS AND MATERIALS Eligible patients had resectable T1-3N0-1M0 thoracic esophageal cancer. After the surgeon explained the treatments in detail, the patients selected either CRT (CRT group) or surgery (OP group). The CRT course consisted of two cycles of cisplatin and fluorouracil with split-course concurrent radiotherapy of 60Gy in 30 fractions. Patients with progressive disease during CRT and/or with persistent or recurrent disease after CRT underwent salvage resection. RESULTS Of 99 eligible patients with squamous cell carcinoma registered between January 2001 and December 2005, 51 selected CRT and 48 selected surgery. Of the patients in the CRT group, 13 (25.5%) underwent esophagectomy as salvage therapy. The 3- and 5-year survival rates were 78.3% and 75.7%, respectively, in the CRT group compared with 56.9% and 50.9%, respectively, in the OP group (p = 0.0169). Patients in the OP group had significantly more metastatic recurrence than those in the CRT group. CONCLUSIONS Treatment outcomes among patients with resectable thoracic esophageal squamous cell carcinoma were comparable or superior after CRT (with salvage therapy if needed) to outcomes after surgery alone.

Evaluation of various deformable image registration algorithms for thoracic images

We evaluated the accuracy of one commercially available and three publicly available deformable image registration (DIR) algorithms for thoracic four-dimensional (4D) computed tomography (CT) images. Five patients with esophagus cancer were studied. Datasets of the five patients were provided by DIR-lab (dir-lab.com) and consisted of thoracic 4D CT images and a coordinate list of anatomical landmarks that had been manually identified. Expert landmark correspondence was used for evaluating DIR spatial accuracy. First, the manually measured displacement vector field (mDVF) was obtained from the coordinate list of anatomical landmarks. Then the automatically calculated displacement vector field (aDVF) was calculated by using the following four DIR algorithms: B-spine implemented in Velocity AI (Velocity Medical, Atlanta, GA, USA), free-form deformation (FFD), Horn–Schunk optical flow (OF) and Demons in DIRART of MATLAB software. Registration error is defined as the difference between mDVF and aDVF. The mean 3D registration errors were 2.7 ± 0.8 mm for B-spline, 3.6 ± 1.0 mm for FFD, 2.4 ± 0.9 mm for OF and 2.4 ± 1.2 mm for Demons. The results showed that reasonable accuracy was achieved in B-spline, OF and Demons, and that these algorithms have the potential to be used for 4D dose calculation, automatic image segmentation and 4D CT ventilation imaging in patients with thoracic cancer. However, for all algorithms, the accuracy might be improved by using the optimized parameter setting. Furthermore, for B-spline in Velocity AI, the 3D registration error was small with displacements of less than ∼10 mm, indicating that this software may be useful in this range of displacements.

Carbon Ion Radiation Therapy Improves the Prognosis of Unresectable Adult Bone and Soft-Tissue Sarcoma of the Head and Neck

PURPOSE To evaluate the safety and efficacy of carbon ion radiotherapy (C-ion RT) with 70.4 GyE for unresectable bone and soft-tissue sarcoma of the adult head and neck. METHODS AND MATERIALS Twenty-seven patients (mean age, 46.2 years) were enrolled in this prospective study on C-ion RT with 70.4 GyE/16 fractions (fr) between April 2001 and February 2008. The primary end points were acute and late reactions of normal tissues, local control rate, and overall survival rate. The secondary end point was efficacy of the treatment in comparison to historical results with 57.6 or 64.0 GyE/16 fr. RESULTS The 3-year local control rate and overall survival rate for all patients were 91.8% (95% confidence interval [CI] = 81.0-100%) and 74.1% (95% CI = 57.5-90.6%), respectively. Acute reaction of Grade 3 or more was observed in only 1 patient. With regard to late reactions, visual loss was observed in 1 patient and a Grade 3 reaction of the maxillary bone was observed in 4 patients. A comparison with historical results revealed that the local control rate with 70.4 GyE was significantly higher than that with 57.6 or 64.0 GyE (3-year, 91.8% vs. 23.6%, p < 0.0001). Furthermore, the overall survival with 70.4 GyE tended to be higher than that with 57.6 or 64.0 GyE (3-year, 74.1% vs. 42.9%, p = 0.09). CONCLUSION C-ion RT with 70.4 GyE/16 fr for bone and soft-tissue sarcoma of the adult head and neck appears to be effective with acceptable toxicities in comparison to conventional RT and C-ion RT with lower doses.

Results of radiation therapy combined with nedaplatin (cis-diammine-glycoplatinum) and 5-Fluorouracil for postoperative locoregional recurrent esophageal cancer

BackgroundAlthough the effectiveness of radiotherapy with concurrent administration of several anti-tumor drugs for postoperative recurrent esophageal cancer has been demonstrated, the results are not satisfactory. The purpose of the present study was to evaluate the effectiveness and safety of radiotherapy combined with nedaplatin and 5-FU for postoperative locoregional (excluding hematogenous metastasis) recurrent esophageal cancer.MethodsIn June 2000, we started a phase II study on treatment of postoperative locoregional recurrent esophageal cancer with radiotherapy (60 Gy/30 fr/6 weeks) combined with chemotherapy consisting of two cycles of nedaplatin (70 mg/m2/2 h) and 5-FU (500 mg/m2/24 h for 5 days).The primary endpoint of the present study was overall survival rate, and the second endpoints were irradiated-field control rate, tumor response and toxicity.ResultsA total of 30 patients were included in this study. The 1-year and 3-year overall survival rates were 60.6% and 56.3%, respectively, with a median survival period of 39.0 months, and the 1-year and 3-year irradiated-field control rates were 86.4% and 72%, respectively. Complete response and partial response were observed in 13.3% and 60.0% of the patients, respectively. Grade 3 or higher leukocytopenia and thrombocytopenia were observed in 30% and 3.3% of the patients, respectively, but renal toxicity of grade 3 or higher was not observed. The regimen was completed in 76.7% of the patients.In univariate analysis, the difference between survival rate in preradiotherapy performance status, recurrent pattern (worse for patients with anastomotic recurrence) and age (worse for younger patients) were statistically significant.ConclusionRadiotherapy combined with nedaplatin and 5-FU is a safe and effective salvage treatment for postoperative locoregional recurrent esophageal cancer.

Initial evaluation of dynamic human imaging using18F-FRP170 as a new PET tracer for imaging hypoxia

Abstract18F-FRP170, 1-(2-fluoro-1-[hydroxymethyl]ethoxy)methyl-2-nitroimidazole, is a new hypoxia imaging agent for positron emission tomography. This compound was synthesized by18F-labeling of RP170, which was developed as a new hydrophilic 2-nitroimidazole analog. In the present study, we analyzed dynamic whole-body imaging in healthy volunteers and dynamic tumor imaging in three patients with lung cancer.Methods: Four healthy male volunteers and three lung cancer patients were enrolled in this study. Volunteers underwent dynamic whole-body scans just after injection of18F-FRP170 for about 90 min, while the lung cancer patients underwent dynamic tumor imaging for about 60 or 120 min. Data are expressed as standardized uptake values (SUV). Regions of interest were placed over images of each organ or tumor to generate time-SUV curves.Results: The series of dynamic whole-body scans showed rapid elimination of18F-FRP170 from the kidneys following elimination from the liver. Very low physiological uptake was observed above the diaphragm.18F-FRP170 uptake in the lung cancer lesion could be visualized clearly from early after injection. The changes of tumor SUV, tumor/blood ratio, or tumor/muscle ratio about 30 min after injection or later were small.Conclusions: Dynamic imaging using18F-FRP170 demonstrated rapid elimination from the kidney, suggesting the high hydrophilicity of this imaging agent. The background activity above the diaphragm was very low, and patients with lung cancer showed clear tumor uptake of18F-FRP170 early after injection.

Treatment outcome of high-dose image-guided intensity-modulated radiotherapy using intra-prostate fiducial markers for localized prostate cancer at a single institute in Japan

BackgroundSeveral studies have confirmed the advantages of delivering high doses of external beam radiotherapy to achieve optimal tumor-control outcomes in patients with localized prostate cancer. We evaluated the medium-term treatment outcome after high-dose, image-guided intensity-modulated radiotherapy (IMRT) using intra-prostate fiducial markers for clinically localized prostate cancer.MethodsIn total, 141 patients with localized prostate cancer treated with image-guided IMRT (76 Gy in 13 patients and 80 Gy in 128 patients) between 2003 and 2008 were enrolled in this study. The patients were classified according to the National Comprehensive Cancer Network-defined risk groups. Thirty-six intermediate-risk patients and 105 high-risk patients were included. Androgen-deprivation therapy was performed in 124 patients (88%) for a median of 11 months (range: 2–88 months). Prostate-specific antigen (PSA) relapse was defined according to the Phoenix-definition (i.e., an absolute nadir plus 2 ng/ml dated at the call). The 5-year actuarial PSA relapse-free survival, the 5-year distant metastasis-free survival, the 5-year cause-specific survival (CSS), the 5-year overall survival (OS) outcomes and the acute and late toxicities were analyzed. The toxicity data were scored according to the Common Terminology Criteria for Adverse Events, version 4.0. The median follow-up was 60 months.ResultsThe 5-year PSA relapse-free survival rates were 100% for the intermediate-risk patients and 82.2% for the high-risk patients; the 5-year actuarial distant metastasis-free survival rates were 100% and 95% for the intermediate- and high-risk patients, respectively; the 5-year CSS rates were 100% for both patient subsets; and the 5-year OS rates were 100% and 91.7% for the intermediate- and high-risk patients, respectively. The Gleason score (<8 vs. ≥8) was significant for the 5-year PSA relapse-free survival on multivariate analysis (p = 0.044). There was no grade 3 or 4 acute toxicity. The incidence of grade 2 acute gastrointestinal (GI) and genitourinary (GU) toxicities were 1.4% and 8.5%, respectively. The 5-year actuarial likelihood of late grade 2–3 GI and GU toxicities were 6% and 6.3%, respectively. No grade 4 GI or GU late toxicity was observed.ConclusionsThese medium-term results demonstrate a good tolerance of high-dose image-guided IMRT. However, further follow-up is needed to confirm the long-term treatment outcomes.

Prognostic factors for local control of stage I non-small cell lung cancer in stereotactic radiotherapy: a retrospective analysis

BackgroundThe purpose of this study is to investigate the prognostic factors of stereotactic radiotherapy for stage I NSCLC to improve outcomes.MethodsStage I non-small cell lung cancer patients who were treated with stereotactic radiotherapy between 2005 and 2009 at our hospital were enrolled in this study. The primary endpoint was local control rate. Survival estimates were calculated from the completion date of radiotherapy using the Kaplan-Meier method. The prognostic factors including patients’ characteristics and dose-volume histogram parameters were evaluated using Cox’s proportional hazard regression model.ResultsEighty patients (81 lesions) treated with 3 dose levels, 48 Gy/4 fractions, 60 Gy/8 fractions and 60 Gy/15 fractions, were enrolled in this study. Median follow-up was 30.4 months (range, 0.3 – 78.5 months). A Cox regression model showed T factor (p = 0.013), biological effective dose calculated from prescribed dose (BED10) (p = 0.048), and minimum dose for PTV (p = 0.013) to be prognostic factors for local control. Three-year overall survival rate and local control rate were 89.9% (T1: 86.8%, T2: 100%) and 89.0% (T1: 97.9%; T2: 64.8%), respectively. When the 3-year local control rates were examined by prescribed doses, they were 100% for the dose per fraction of 48 Gy /4 fractions (105.6 Gy BED10), 82.1% for 60 Gy/8 fractions (105 Gy BED10), and 57.1% for 60 Gy/15 fractions (84 Gy BED10). The median value of the minimum dose for PTV (%) was 89.88 (%), and the 3-year local control rates were 100% in those with the minimum dose for PTV (%) ≥ 89.88% and 79.2% in those with the minimum dose for PTV (%) < 89.88%.ConclusionsOur results suggest that T factor, BED10, and minimum dose for PTV influence the local control rate. Local control rate can be improved by securing the minimum dose for PTV.

Long-term bresults of radiotherapy combined with nedaplatin and 5-fluorouracil for postoperative loco-regional recurrent esophageal cancer: update on a phase II study

BackgroundIn 2006, we reported the effectiveness of chemoradiotherapy for postoperative recurrent esophageal cancer with a median observation period of 18 months. The purpose of the present study was to update the results of radiotherapy combined with nedaplatin and 5-fluorouracil (5-FU) for postoperative loco-regional recurrent esophageal cancer.MethodsBetween 2000 and 2004, we performed a phase II study on treatment of postoperative loco-regional recurrent esophageal cancer with radiotherapy (60 Gy/30 fractions/6 weeks) combined with chemotherapy consisting of two cycles of nedaplatin (70 mg/m2/2 h) and 5-FU (500 mg/m2/24 h for 5 days).The primary endpoint was overall survival rate, and the secondary endpoints were progression-free survival rate, irradiated-field control rate and chronic toxicity.ResultsA total of 30 patients were enrolled in this study. The regimen was completed in 76.7% of the patients. The median observation period for survivors was 72.0 months. The 5-year overall survival rate was 27.0% with a median survival period of 21.0 months. The 5-year progression-free survival rate and irradiated-field control rate were 25.1% and 71.5%, respectively. Grade 3 or higher late toxicity was observed in only one patient. Two long-term survivors had gastric tube cancer more than 5 years after chemoradiotherapy.Pretreatment performance status, pattern of recurrence (worse for patients with anastomotic recurrence) and number of recurrent lesions (worse for patients with multiple recurrent lesions) were statistically significant prognostic factors for overall survival.ConclusionsRadiotherapy combined with nedaplatin and 5-FU is a safe and effective salvage treatment for postoperative loco-regional recurrent esophageal cancer. However, the prognosis of patients with multiple regional recurrence or anastomotic recurrence is very poor.

Evaluation of accuracy of B-spline transformation-based deformable image registration with different parameter settings for thoracic images

Deformable image registration (DIR) is fundamental technique for adaptive radiotherapy and image-guided radiotherapy. However, further improvement of DIR is still needed. We evaluated the accuracy of B-spline transformation-based DIR implemented in elastix. This registration package is largely based on the Insight Segmentation and Registration Toolkit (ITK), and several new functions were implemented to achieve high DIR accuracy. The purpose of this study was to clarify whether new functions implemented in elastix are useful for improving DIR accuracy. Thoracic 4D computed tomography images of ten patients with esophageal or lung cancer were studied. Datasets for these patients were provided by DIR-lab (dir-lab.com) and included a coordinate list of anatomical landmarks that had been manually identified. DIR between peak-inhale and peak-exhale images was performed with four types of parameter settings. The first one represents original ITK (Parameter 1). The second employs the new function of elastix (Parameter 2), and the third was created to verify whether new functions improve DIR accuracy while keeping computational time (Parameter 3). The last one partially employs a new function (Parameter 4). Registration errors for these parameter settings were calculated using the manually determined landmark pairs. 3D registration errors with standard deviation over all cases were 1.78 (1.57), 1.28 (1.10), 1.44 (1.09) and 1.36 (1.35) mm for Parameter 1, 2, 3 and 4, respectively, indicating that the new functions are useful for improving DIR accuracy, even while maintaining the computational time, and this B-spline-based DIR could be used clinically to achieve high-accuracy adaptive radiotherapy.

Evaluation of On-Board kV Cone Beam Computed Tomography–Based Dose Calculation With Deformable Image Registration Using Hounsfield Unit Modifications

PURPOSE The purpose of this study was to estimate the accuracy of the dose calculation of On-Board Imager (Varian, Palo Alto, CA) cone beam computed tomography (CBCT) with deformable image registration (DIR), using the multilevel-threshold (MLT) algorithm and histogram matching (HM) algorithm in pelvic radiation therapy. METHODS AND MATERIALS One pelvis phantom and 10 patients with prostate cancer treated with intensity modulated radiation therapy were studied. To minimize the effect of organ deformation and different Hounsfield unit values between planning CT (PCT) and CBCT, we modified CBCT (mCBCT) with DIR by using the MLT (mCBCT(MLT)) and HM (mCBCT(HM)) algorithms. To evaluate the accuracy of the dose calculation, we compared dose differences in dosimetric parameters (mean dose [D(mean)], minimum dose [D(min)], and maximum dose [D(max)]) for planning target volume, rectum, and bladder between PCT (reference) and CBCTs or mCBCTs. Furthermore, we investigated the effect of organ deformation compared with DIR and rigid registration (RR). We determined whether dose differences between PCT and mCBCTs were significantly lower than in CBCT by using Student t test. RESULTS For patients, the average dose differences in all dosimetric parameters of CBCT with DIR were smaller than those of CBCT with RR (eg, rectum; 0.54% for DIR vs 1.24% for RR). For the mCBCTs with DIR, the average dose differences in all dosimetric parameters were less than 1.0%. CONCLUSIONS We evaluated the accuracy of the dose calculation in CBCT, mCBCT(MLT), and mCBCT(HM) with DIR for 10 patients. The results showed that dose differences in D(mean), D(min), and D(max) in mCBCTs were within 1%, which were significantly better than those in CBCT, especially for the rectum (P<.05). Our results indicate that the mCBCT(MLT) and mCBCT(HM) can be useful for improving the dose calculation for adaptive radiation therapy.