Hiroyoshi Akimoto

Stereotactic body radiotherapy for lung metastases as oligo-recurrence: a single institutional study.

The purpose of this study was to investigate clinical outcomes following stereotactic body radiotherapy (SBRT) for lung metastases as oligo-recurrence. From May 2003 to June 2014, records for 66 patients with 76 oligo-recurrences in the lungs treated with SBRT were retrospectively reviewed. Oligo-recurrence primary sites and patient numbers were as follows: lungs, 31; colorectal, 13; head and neck, 10; esophagus, 3; uterus, 3; and others, 6. The median SBRT dose was 50 Gy (range, 45–60 Gy) administered in a median of 5 (range, 5–9) fractions. All patients received SBRT, with no acute toxicity. Surviving patients had a median follow-up time of 36.5 months. The 3-year rates of local control, overall survival and disease-free survival were 90.6%, 76.0% and 53.7%, respectively. Longer disease-free interval from initial treatment to SBRT, and non-colorectal cancer were both associated with favorable outcomes. Disease progression after SBRT occurred in 31 patients, most with distant metastases (n = 24) [among whom, 87.5% (n = 21) had new lung metastases]. Among these 21 patients, 12 were judged as having a second oligo-recurrence. Additional SBRT was performed for these 12 patients, and all 12 tumors were controlled without disease progression. Three patients (4.5%) developed Grade 2 radiation pneumonitis. No other late adverse events of Grade ≥2 were identified. Thus, SBRT for oligo-recurrence achieved acceptable tumor control, with additional SBRT also effective for selected patients with a second oligo-recurrence after primary SBRT.

Clinical outcome of stereotactic body radiotherapy for primary and oligometastatic lung tumors: a single institutional study with almost uniform dose with different five treatment schedules

BackgroundTo evaluate clinical outcomes of stereotactic body radiotherapy (SBRT) for localized primary and oligometastatic lung tumors by assessing efficacy and safety of 5 regimens of varying fraction size and number.MethodsOne-hundred patients with primary lung cancer (n = 69) or oligometastatic lung tumors (n = 31), who underwent SBRT between May 2003 and August 2010, were included. The median age was 75 years (range, 45–88). Of them, 98 were judged to have medically inoperable disease, predominantly due to chronic illness or advanced age. SBRT was performed using 3 coplanar and 3 non-coplanar fixed beams with a standard linear accelerator. Fraction sizes were escalated by 1 Gy, and number of fractions given was decreased by 1 for every 20 included patients. Total target doses were between 50 and 56 Gy, administered as 5–9 fractions. The prescribed dose was defined at the isocenter, and median overall treatment duration was 10 days (range, 5–22).ResultsThe median follow-up was 51.1 months for survivors. The 3-year local recurrence rates for primary lung cancer and oligometastasis was 6 % and 3 %, respectively. The 3-year local recurrence rates for tumor sizes ≤3 cm and >3 cm were 3 % and 14 %, respectively (p = 0.124). Additionally, other factors (fraction size, total target dose, and BED10) were not significant predictors of local control. Radiation pneumonia (≥ grade 2) was observed in 2 patients. Radiation-induced rib fractures were observed in 22 patients. Other late adverse events of greater than grade 2 were not observed.ConclusionWithin this dataset, we did not observe a dose response in BED10 values between 86.4 and 102.6 Gy. SBRT with doses between 50 and 56 Gy, administered over 5–9 fractions achieved acceptable tumor control without severe complications.

Correlation between tumor size and blood volume in lung tumors: a prospective study on dual-energy gemstone spectral CT imaging

The purpose of this study was to investigate the relationship between tumor size and blood volume for patients with lung tumors, using dual-energy computed tomography (DECT) and a gemstone spectral imaging (GSI) viewer. During the period from March 2011 to March 2013, 50 patients with 57 medically inoperable lung tumors underwent DECT before stereotactic body radiotherapy (SBRT) of 50–60 Gy in 5–6 fractions. DECT was taken for pretreatment evaluation. The region-of-interest for a given spatial placement of the tumors was set, and averages for CT value, water density and iodine density were compared with tumor size. The average values for iodine density in tumors of ≤2 cm, 2–3 cm, and >3 cm maximum diameter were 24.7, 19.6 and 16.0 (100 µg/cm3), respectively. The average value of the iodine density was significantly lower in larger tumors. No significant correlation was detected between tumor size and average CT value or between tumor size and average water density. Both the average water density and the average CT value were affected by the amount of air in the tumor, but the average iodine density was not affected by air in the tumor. The average water density and the average CT value were significantly correlated, but the average iodine density and the average CT value showed no significant correlation. The blood volume of tumors can be indicated by the average iodine density more accurately than it can by the average CT value. The average iodine density as assessed by DECT might be a non-invasive and quantitative assessment of the radio-resistance ascribable to the hypoxic cell population in a tumor.

LW6, a hypoxia-inducible factor 1 inhibitor, selectively induces apoptosis in hypoxic cells through depolarization of mitochondria in A549 human lung cancer cells

Hypoxia-inducible factor 1 (HIF-1) activates the transcription of genes that act upon the adaptation of cancer cells to hypoxia. LW6, an HIF-1 inhibitor, was hypothesized to improve resistance to cancer therapy in hypoxic tumors by inhibiting the accumulation of HIF-1α. A clear anti-tumor effect under low oxygen conditions would indicate that LW6 may be an improved treatment strategy for cancer in hypoxia. In the present study, the HIF-1 inhibition potential of LW6 on the growth and apoptosis of A549 lung cancer cells in association with oxygen availability was evaluated. LW6 was observed to inhibit the expression of HIF-1α induced by hypoxia in A549 cells at 20 mM, independently of the von Hippel-Lindau protein. In addition, at this concentration, LW6 induced hypoxia-selective apoptosis together with a reduction in the mitochondrial membrane potential. The intracellular reactive oxygen species levels increased in LW6-treated hypoxic A549 cells and LW6 induced a hypoxia-selective increase of mitochondrial O2•−. In conclusion, LW6 inhibited the growth of hypoxic A549 cells by affecting the mitochondria. The inhibition of the mitochondrial respiratory chain is suggested as a potentially effective strategy to target apoptosis in cancer cells.

Prognostic impact of average iodine density assessed by dual-energy spectral imaging for predicting lung tumor recurrence after stereotactic body radiotherapy.

The purpose of this study was to investigate the prognostic significance of average iodine density as assessed by dual-energy computed tomography (DE-CT) for lung tumors treated with stereotactic body radiotherapy (SBRT). From March 2011 to August 2014, 93 medically inoperable patients with 74 primary lung cancers and 19 lung metastases underwent DE-CT prior to SBRT of a total dose of 45–60 Gy in 5–10 fractions. Of these 93 patients, nine patients had two lung tumors. Thus, 102 lung tumors were included in this study. DE-CT was performed for pretreatment evaluation. Regions of interest were set for the entire tumor, and average iodine density was obtained using a dedicated imaging software and evaluated with regard to local control. The median follow-up period was 23.4 months (range, 1.5–54.5 months). The median value of the average iodine density was 1.86 mg/cm3 (range, 0.40–9.27 mg/cm3). Two-year local control rates for the high and low average iodine density groups divided by the median value of the average iodine density were 96.9% and 75.7% (P = 0.006), respectively. Tumors with lower average iodine density showed a worse prognosis, possibly reflecting a hypoxic cell population in the tumor. The average iodine density exhibited a significant impact on local control. Our preliminary results indicate that iodine density evaluated using dual-energy spectral CT may be a useful, noninvasive and quantitative assessment of radio-resistance caused by presumably hypoxic cell populations in tumors.

Impact of pretreatment whole-tumor perfusion computed tomography and 18F-fluorodeoxyglucose positron emission tomography/computed tomography measurements on local control of non-small cell lung cancer treated with stereotactic body radiotherapy.

This study aimed to investigate the correlation between the average iodine density (AID) detected by dual-energy computed tomography (DE-CT) and the maximum standardized uptake value (SUVmax) yielded by [18F] fluorodeoxyglucose positron emission tomography (18F-FDG PET) for non–small cell lung cancer (NSCLC) treated with stereotactic body radiotherapy (SBRT). Seventy-four patients with medically inoperable NSCLC who underwent both DE-CT and 18F-FDG PET/CT before SBRT (50‒60 Gy in 5‒6 fractions) were followed up after a median interval of 24.5 months. Kaplan–Meier analysis was used to determine associations between local control (LC) and variables, including AID, SUVmax, tumor size, histology, and prescribed dose. The median AID and SUVmax were 18.64 (range, 1.18–45.31) (100 µg/cm3) and 3.2 (range, 0.7–17.6), respectively. No correlation was observed between AID and SUVmax. Two-year LC rates were 96.2% vs 75.0% (P = 0.039) and 72.0% vs 96.2% (P = 0.002) for patients classified according to high vs low AID or SUVmax, respectively. Two-year LC rates for patients with adenocarcinoma vs squamous cell carcinoma vs unknown cancer were 96.4% vs 67.1% vs 92.9% (P = 0.008), respectively. Multivariate analysis identified SUVmax as a significant predictor of LC. The 2-year LC rate was only 48.5% in the subgroup of lower AID and higher SUVmax vs >90% (range, 94.4–100%) in other subgroups (P = 0.000). Despite the short follow-up period, a reduction in AID and subsequent increase in SUVmax correlated significantly with local failure in SBRT-treated NSCLC patients. Further studies involving larger populations and longer follow-up periods are needed to confirm these results.

Clinical results of accelerated hypofractionated radiotherapy for central-type small lung tumours

PURPOSE We evaluated the efficacy and toxicity of accelerated hypofractionated radiotherapy (ahypof-rt) for central-type small lung tumours. METHODS Between November 2006 and January 2015, 40 patients with central-type small lung tumours underwent ahypof-rt delivered using 10 MV X-rays and a coplanar 3-field technique. The number of fractions ranged from 24 to 28, with a fraction size of 2.5-3 Gy. A total dose of 69-75 Gy to the isocentre of the planning target volume was administered to each patient. Cumulative survival and local control rates were calculated using the Kaplan-Meier method. RESULTS The 27 men and 13 women enrolled in the study had a median age of 79 years (range: 60-87 years). The tumour stage was T1a in 9 patients, T1b in 17 patients, and T2a in 14 patients, with a median size of 26.5 cm (range: 11-49 cm). The median follow-up period was 23 months. A complete response was achieved in 3 patients (7.5%), and a partial response, in 17 patients (42.5%). The overall 2-year and 3-year local control rates were 87.3% and 81.8% respectively; the 2-year and 3-year overall survival rates were 78.9% and 66.7% respectively. Grade 3 pneumonitis occurred in 3 patients; no other severe adverse events (≥grade 3) were observed in any patient. CONCLUSIONS Accelerated hypofractionated radiotherapy using a fraction size of 2.5-3 Gy was highly safe and can be a more effective treatment option than conventional radiotherapy for patients with central-type small lung tumours.

SU‐F‐J‐131: Reproducibility of Positioning Error Due to Temporarily Indwelled Urethral Catheter for Urethra‐Sparing Prostate IMRT

PURPOSE The purpose of this study was to prospectively assess the reproducibility of positioning errors due to temporarily indwelled catheter in urethra-sparing image-guided (IG) IMRT. METHODS Ten patients received urethra-sparing prostate IG-IMRT with implanted fiducials. After the first CT scan was performed in supine position, 6-Fr catheter was indwelled into urethra, and the second CT images were taken for planning. While the PTV received 80 Gy, 5% dose reduction was applied for the urethral PRV along the catheter. Additional CT scans were also performed at 5th and 30th fraction. Positions of interests (POIs) were set on posterior edge of prostate at beam isocenter level (POI1) and cranial and caudal edge of prostatic urethra on the post-indwelled CT images. POIs were copied into the pre-indwelled, 5th and 30th fractions CT images after fiducial matching on these CT images. The deviation of each POI between pre- and post-indwelled CT and the reproducibility of prostate displacement due to catheter were evaluated. RESULTS The deviation of POI1 caused by the indwelled catheter to the directions of RL/AP/SI (mm) was 0.20±0.27/-0.64±2.43/1.02±2.31, respectively, and the absolute distances (mm) were 3.15±1.41. The deviation tends to be larger if closer to the caudal edge of prostate. Compared with the pre-indwelled CT scan, a median displacement of all POIs (mm) were 0.3±0.2/2.2±1.1/2.0±2.6 in the post-indwelled, 0.4±0.4/3.4±2.1/2.3±2.6 in 5th, and 0.5±0.5/1.7±2.2/1.9±3.1 in 30th fractions CT scan with a similar data distribution. There were 6 patients with 5-mm-over displacement in AP and/or CC directions. CONCLUSION Reproducibility of positioning errors due to temporarily indwelling catheter was observed. Especially in case of patients with unusually large shifts by indwelling catheter at the planning process, treatment planning should be performed by using the pre-indwelled CT images with transferred contour of the urethra identified by post-indwelled CT images.

SU-E-J-40: Improving Uncertainty of Prostate Positioning by Using Implanted Fiducial Marker-Based Hybrid Evaluation Combined with KV Portal Imaging and CBCT for Prostate IMRT

Purpose The aim of this work was to present our single-institution experience with fiducial marker-based hybrid evaluation of prostate positioning combined with orthogonal kV portal image which inform the central position of prostate and CBCT which provides the information on localization of the peripheral structures. Methods Twenty-five patients received prostate IMRT with daily localization by use of implanted fiducials. Orthogonal kV portal imaging and CBCT preceded all 977 treatments. After shifts in the AP, SI, and LR dimensions were made from kV imaging, following another shifts were made when more than 2-mm prostate deviation as total sum of all dimensions were detected by CBCT. Post-treatment kV imaging and CBCT were also obtained in 203 treatments (21%). Shifts between two techniques were analyzed, and compared by Bland-Altman limits of agreement. Intrafraction motion and PTV margin were determined from shifts between pre- and post-treatment in each technique. Results Pre-treatment isocenter shift were made based on CBCT in addition to kV imaging in 315 (32%) treatments. Mean differences between kV imaging and CBCT in the AP/SI/LR were −0.10±0.93/− 0.06±0.91/0.15±0.51 mm. The correlation between these techniques was follows: R2 = 0.90, 0.93, 0.94. Bland-Altman 95% confidence intervals were −1.7 to 1.9/−1.7 to 1.8/−1.2 to 0.8 mm, without significant trends. Intrafraction motion for prostate obtained from pre- and post-CBCT were 0.00±0.15/0.02±1.49/0.15±0.64 mm, which were smaller than the results from kV imaging (0.42±1.90/0.12±1.98/0.26±0.80 mm). PTV margins calculated from the results of CBCT were also smaller than kV imaging (3.95 mm vs 5.15 mm, 4.02 mm vs 5.34 mm, 1.75 mm vs 2.18 mm). Conclusion Hybrid evaluation combined with identification of cranial and caudal edge of prostate by using CBCT compensates the uncertainty of prostate positioning originated from independent utilization of kV portal imaging, which enables to set PTV margins that reflect more realistic intrafraction organ motion.