Rumiko Kinoshita

Three-Dimensional Intrafractional Motion of Breast During Tangential Breast Irradiation Monitored With High-Sampling Frequency Using a Real-Time Tumor-Tracking Radiotherapy System

PURPOSE To evaluate the three-dimensional intrafraction motion of the breast during tangential breast irradiation using a real-time tracking radiotherapy (RT) system with a high-sampling frequency. METHODS AND MATERIALS A total of 17 patients with breast cancer who had received breast conservation RT were included in this study. A 2.0-mm gold marker was placed on the skin near the nipple of the breast for RT. A fluoroscopic real-time tumor-tracking RT system was used to monitor the marker. The range of motion of each patient was calculated in three directions. RESULTS The mean +/- standard deviation of the range of respiratory motion was 1.0 +/- 0.6 mm (median, 0.9; 95% confidence interval [CI] of the marker position, 0.4-2.6), 1.3 +/- 0.5 mm (median, 1.1; 95% CI, 0.5-2.5), and 2.6 +/- 1.4 (median, 2.3; 95% CI, 1.0-6.9) for the right-left, craniocaudal, and anteroposterior direction, respectively. No correlation was found between the range of motion and the body mass index or respiratory function. The mean +/- standard deviation of the absolute value of the baseline shift in the right-left, craniocaudal, and anteroposterior direction was 0.2 +/- 0.2 mm (range, 0.0-0.8 mm), 0.3 +/- 0.2 mm (range, 0.0-0.7 mm), and 0.8 +/- 0.7 mm (range, 0.1-1.8 mm), respectively. CONCLUSION Both the range of motion and the baseline shift were within a few millimeters in each direction. As long as the conventional wedge-pair technique and the proper immobilization are used, the intrafraction three-dimensional change in the breast surface did not much influence the dose distribution.

What is the appropriate size criterion for proton radiotherapy for hepatocellular carcinoma? A dosimetric comparison of spot-scanning proton therapy versus intensity-modulated radiation therapy

BackgroundWe performed a dosimetric comparison of spot-scanning proton therapy (SSPT) and intensity-modulated radiation therapy (IMRT) for hepatocellular carcinoma (HCC) to investigate the impact of tumor size on the risk of radiation induced liver disease (RILD).MethodsA number of alternative plans were generated for 10 patients with HCC. The gross tumor volumes (GTV) varied from 20.1 to 2194.5 cm3. Assuming all GTVs were spherical, the nominal diameter was calculated and ranged from 3.4 to 16.1 cm. The prescription dose was 60 Gy for IMRT or 60 cobalt Gy-equivalents for SSPT with 95% planning target volume (PTV) coverage. Using IMRT and SSPT techniques, extensive comparative planning was conducted. All plans were evaluated by the risk of RILD estimated using the Lyman-normal-tissue complication probability model.ResultsFor IMRT the risk of RILD increased drastically between 6.3–7.8 cm nominal diameter of GTV. When the nominal diameter of GTV was more than 6.3 cm, the average risk of RILD was 94.5% for IMRT and 6.2% for SSPT.ConclusionsRegarding the risk of RILD, HCC can be more safely treated with SSPT, especially if its nominal diameter is more than 6.3 cm.

β1-integrin via NF-κB signaling is essential for acquisition of invasiveness in a model of radiation treated in situ breast cancer

IntroductionDuctal carcinoma in situ (DCIS) is characterized by non-invasive cancerous cell growth within the breast ducts. Although radiotherapy is commonly used in the treatment of DCIS, the effect and molecular mechanism of ionizing radiation (IR) on DCIS are not well understood, and invasive recurrence following radiotherapy remains a significant clinical problem. This study investigated the effects of IR on a clinically relevant model of Akt-driven DCIS and identified possible molecular mechanisms underlying invasive progression in surviving cells.MethodsWe measured the level of phosphorylated-Akt (p-Akt) in a cohort of human DCIS specimens by immunohistochemistry (IHC) and correlated it with recurrence risk. To model human DCIS, we used Akt overexpressing human mammary epithelial cells (MCF10A-Akt) which, in three-dimensional laminin-rich extracellular matrix (lrECM) and in vivo, form organotypic DCIS-like lesions with lumina expanded by pleiomorphic cells contained within an intact basement membrane. In a population of cells that survived significant IR doses in three-dimensional lrECM, a malignant phenotype emerged creating a model for invasive recurrence.ResultsP-Akt was up-regulated in clinical DCIS specimens and was associated with recurrent disease. MCF10A-Akt cells that formed DCIS-like structures in three-dimensional lrECM showed significant apoptosis after IR, preferentially in the luminal compartment. Strikingly, when cells that survived IR were repropagated in three-dimensional lrECM, a malignant phenotype emerged, characterized by invasive activity, up-regulation of fibronectin, α5β1-integrin, matrix metalloproteinase-9 (MMP-9) and loss of E-cadherin. In addition, IR induced nuclear translocation and binding of nuclear factor-kappa B (NF-κB) to the β1-integrin promoter region, associated with up-regulation of α5β1-integrins. Inhibition of NF-κB or β1-integrin signaling abrogated emergence of the invasive activity.ConclusionsP-Akt is up-regulated in some human DCIS lesions and is possibly associated with recurrence. MCF10A-Akt cells form organotypic DCIS-like lesions in three-dimensional lrECM and in vivo, and are a plausible model for some forms of human DCIS. A population of Akt-driven DCIS-like spheroids that survive IR progresses to an invasive phenotype in three-dimensional lrECM mediated by β1-integrin and NF-κB signaling.

Evaluation of inter-observer variability of bladder boundary delineation on cone-beam CT

BackgroundIn-room cone-beam computerized tomography (CBCT) imaging is a promising method to reduce setup errors, especially in organs such as the bladder that often have large intrafractional variations due to organ movement. CBCT image quality is limited by low contrast and imaging artifacts, but few data have been reported about inter-observer variability of bladder boundary delineation on CBCT. The aim of this work was to analyze and evaluate the inter-observer contouring uncertainties of bladder boundary delineation on CBCT images in a prospective fashion.MethodsFive radiation oncologists contoured 10 bladders using the CBCT datasets of consecutive 10 patients (including 4 females) who were irradiated to the pelvic region. Prostates were also contoured in male patients. Patients who had had prostatectomy were excluded. The coefficient of variation (COV), conformity index (CIgen), and coordinates of center-of-mass (COM) of the bladder and prostate were calculated for each patient.ResultsThe mean COV for the bladder and prostate was 0.08 and 0.20, respectively. The mean CIgen of the bladder and prostate was 0.81 and 0.66, respectively. The root mean square (RMS) of the inter-observer standard deviation (σ) of the COM displacement in the left-right (LR) and anterior-posterior (AP) direction was 0.79, 0.87 and 0.54 for the bladder and 0.63, 0.99 and 1.72 for the prostate. Regarding the mean COV and CIgen for the bladder, the differences between males and females were not significant.ConclusionsInter-observer variability for bladder delineation on CBCT images was substantially small regardless of gender. We believe that our results support the applicability of CBCT in adaptive radiotherapy for bladder cancer.

NTCP modeling analysis of acute hematologic toxicity in whole pelvic radiation therapy for gynecologic malignancies : A dosimetric comparison of IMRT and spot-scanning proton therapy (SSPT)

PURPOSE This treatment planning study was conducted to determine whether spot scanning proton beam therapy (SSPT) reduces the risk of grade ⩾3 hematologic toxicity (HT3+) compared with intensity modulated radiation therapy (IMRT) for postoperative whole pelvic radiation therapy (WPRT). METHODS AND MATERIALS The normal tissue complication probability (NTCP) of the risk of HT3+ was used as an in silico surrogate marker in this analysis. IMRT and SSPT plans were created for 13 gynecologic malignancy patients who had received hysterectomies. The IMRT plans were generated using the 7-fields step and shoot technique. The SSPT plans were generated using anterior-posterior field with single field optimization. Using the relative biological effectives (RBE) value of 1.0 for IMRT and 1.1 for SSPT, the prescribed dose was 45Gy(RBE) in 1.8Gy(RBE) per fractions for 95% of the planning target volume (PTV). The homogeneity index (HI) and the conformity index (CI) of the PTV were also compared. RESULTS The bone marrow (BM) and femoral head doses using SSPT were significantly lower than with IMRT. The NTCP modeling analysis showed that the risk of HT3+ using SSPT was significantly lower than with IMRT (NTCP=0.04±0.01 and 0.19±0.03, p=0.0002, respectively). There were no significant differences in the CI and HI of the PTV between IMRT and SSPT (CI=0.97±0.01 and 0.96±0.02, p=0.3177, and HI=1.24±0.11 and 1.27±0.05, p=0.8473, respectively). CONCLUSION The SSPT achieves significant reductions in the dose to BM without compromising target coverage, compared with IMRT. The NTCP value for HT3+ in SSPT was significantly lower than in IMRT.

High-dose-rate Intra-cavitary Brachytherapy Combined with External Beam Radiation Therapy for Under 40-Year-old Patients with Invasive Uterine Cervical Carcinoma: Clinical Outcomes in 118 Patients in a Japanese Multi-institutional Study, JASTRO

BACKGROUND The current study was designed to evaluate the clinical outcomes of curative intent radiation therapy for young patients with invasive uterine cervical carcinoma in Japan. METHODS One hundred and eighteen patients aged ≤40 were registered in the multi-institutional study of the Japanese Society of Therapeutic Radiology and Oncology (JASTRO) from 26 major institutions in Japan. The age range was 24-39 years and the maximum tumor diameter was 2.0-9.2 cm. The International Federation of Gynecology and Obstetrics clinical stages were Ib, IIa, IIb, IIIa, IIIb and IVa in 17, 6, 40, 2, 50 and 3, respectively. Curative intent radiation therapy consisted of the combination of external beam radiation therapy and high-dose rate intra-cavitary brachytherapy. The total dose of external beam radiation therapy ranged between 44 and 68 Gy. Both the median and mode of total high-dose-rate intra-cavitary brachytherapy dose to point A were 24 Gy in four fractions. Ninety-six patients (58%) received chemotherapy. RESULTS The 5-year overall survival rate and local control rate of all patients were 61 and 65%, respectively. The 5-year overall survival rates of International Federation of Gynecology and Obstetrics Stage Ib, IIa, IIb, IIIa, IIIb and IVa were 88, 100, 75, 100, 37 and 0%, respectively. The 5-year local control rates of International Federation of Gynecology and Obstetrics Stage Ib, IIa, IIb, IIIa, IIIb and IVa were 82, 75, 75, 100, 51 and 0%, respectively. Sixteen patients experienced grade 3 or greater late radiation morbidity. CONCLUSIONS The 5-year overall survival rate of young patients with Stage IIIb was comparatively low at 37%.

High Dose Three-Dimensional Conformal Boost Using the Real-Time Tumor Tracking Radiotherapy System in Cervical Cancer Patients Unable to Receive Intracavitary Brachytherapy

Purpose The purpose of this study is to evaluate the clinical results of treatment with a high dose of 3-dimensional conformal boost (3DCB) using a real-time tracking radiation therapy (RTRT) system in cervical cancer patients. Materials and Methods Between January 2001 and December 2004, 10 patients with cervical cancer were treated with a high dose 3DCB using RTRT system. Nine patients received whole pelvis radiation therapy (RT) with a median dose of 50 Gy (range, 40-50 Gy) before the 3DCB. The median dose of the 3DCB was 30 Gy (range, 25-30 Gy). Eight patients received the 3DCB twice a week with a daily fraction of 5 Gy. The determined endpoints were tumor response, overall survival, local failure free survival, and distant metastasis free survival. The duration of survival was calculated from the time of the start of radiotherapy. Results All patients were alive at the time of analysis and the median follow-up was 17.6 months (range, 4.9-27.3 months). Complete response was achieved in nine patients and one patient had a partial response. The 1- and 2-year local failure free survival was 78.8% and 54%, respectively. The 1- and 2-year distant metastasis free survival was 90% and 72%, respectively. Late toxicity of a grade 2 rectal hemorrhage was seen in one patient. A subcutaneous abscess was encountered in one patient. Conclusion The use of the high dose 3DCB in the treatment of cervical cancer is safe and feasible where intracavitary brachytherapy (ICBT) is unable to be performed. The escalation of the 3DCB dose is currently under evaluation.

Prognostic significance of clusterin expression in advanced-stage cervical cancer treated with curative intended radiotherapy.

Objective Overexpression of clusterin (CLU), an antiapoptotic molecule, has been reported to induce resistance to radiotherapy (RT) in a variety of cancer cell types. The aim of this study was to evaluate the significance of CLU expression to predict survival of patients with advanced-stage cervical cancer who received curative intended RT. Methods Biopsy tissue specimens of advanced-stage cervical cancer before curative intended RT were obtained from 34 patients who were treated at Hokkaido University Hospital between 1998 and 2008 and whose complete medical records were available. The expression of CLU protein was analyzed by immunohistochemistry. Findings were evaluated in relation to several clinicopathological factors. Survival analyses were performed using the Kaplan-Meier curves and the log-rank test. Independent prognostic factors were determined by multivariate Cox regression analysis. Results Clusterin protein was mainly present in the cytoplasm of cervical cancer cells. The expression of CLU protein in cervical cancer tissues before curative intended RT was not significantly related to any clinicopathological factors analyzed, including age, clinical stage, histologic type, and response to RT. Univariate analysis on prognostic factors showed that histologic type (P = 0.001), and CLU expression (P = 0.02) were related to survival. Multivariate analysis revealed that both histologic type (P = 0.002), and CLU expression (P = 0.02) were independent prognostic factors for overall survival. Conclusion We conclude that CLU could be a new molecular marker to predict overall survival of patients with advanced-stage cervical cancer treated with curative intended RT.

Prospective study to evaluate the safety of the world-first spot-scanning dedicated, small 360-degree gantry, synchrotron-based proton beam therapy system

Abstract This is a report of a single-institution prospective study evaluating the safety of a spot-scanning dedicated, small 360-degree gantry, synchrotron-based proton beam therapy (PBT) system. Data collection was performed for 56 patients with 59 treatment sites who received proton beam therapy at Hokkaido University Hospital between March 2014 and July 2015. Forty-one patients were male and 15 were female. The median age was 66 years. The primary lesion sites were prostate (n = 17), bone/soft tissue (n = 10), liver (n = 7), lung (n = 6), central nervous system (n = 5), colon (n = 2), pancreas (n = 2), kidney (n = 2) and others (n = 5). Chemotherapy was administered in 11 patients. The prescribed total dose was from 20 to 76 GyE (Radiobiological equivalent dose, RBE = 1.1), with the median dose of 65 GyE in 4 to 35 fractions. No PBT-related Common Terminology Criteria for Adverse Events Grade 4 or 5 toxicities were observed; the incidence of early PBT-related Grade 4 adverse events was 0% (95% confidence interval 0 to 6.38%). The most common Grade 3 toxicities were hematologic toxicity (12.5%) unlikely to be related to the PBT. One patient developed a left femoral neck fracture (Grade 3) at 14.5 months after PBT for chondrosarcoma of the left pelvis. The pathological findings showed no other malignancies, suggesting that it was possibly related to the PBT. In conclusion, the spot-scanning dedicated, synchrotron-based PBT system is feasible, but further studies on its long-term safety and efficacy are warranted.

Improvement of tracking accuracy and stability by recursive image processing in real-time tumor-tracking radiotherapy system

In the real-time tumor-tracking radiotherapy (RTRT) system, the fiducial markers are inserted in or near the target tumor in order monitor the respiratory-induced motion of tumors. During radiation treatment, the markers are detected by continuous fluoroscopy operated at 30 frames/sec. The marker position is determined by means of a template pattern matching technique which is based on the normalized cross correlation. With high tube voltage, large current and long exposure, the fiducial marker will be recognized accurately, however, the radiation dose due to X-ray fluoroscopy increases. On the other hand, by decreasing the fluoroscopy parameter settings, the fiducial marker could be lost because the effect of statistical noise is increased. In the respiratory-gated radiotherapy, the error of the image guidance will induce the reduction of the irradiation efficiency and accuracy. In order to track the marker stably and accurately in low dose fluoroscopy, we propose the application of a recursive filter. The effectiveness of the image processing is investigated by tracking the static marker and the dynamic marker. The results suggest that the stability and the accuracy of the marker tracking can be improved by applying the recursive image filter in low dose imaging.