Clinical Evaluation of Onrad, A New Low-cost Version of TomoTherapy that Uses Only Static Beams.

OBJECTIVE: This study evaluated the clinical feasibility of a new low-cost TomoTherapy system (OnradTM) and compared it with low-cost linear accelerator models (linacs). METHODS: Various aspects of treatment and cost were compared between Onrad and linacs for 3-dimensional radiotherapy (3DCRT). Dosimetric comparisons of 10 patients each with breast, stage III lung, prostate, head and neck, and cervical cancers were carried out (total 100 plans). RESULTS: Onrad had advantages in terms of availability of long treatment fields and a smaller mechanical footprint. For breast cancers and lung cancers, target dose homogeneity in Onrad plans was better than that in 3DCRT. In the prostate plans, Onrad plans provided superior D95, conformity and homogeneity. The rectum doses of Onrad plans were lower than those with 3DCRT. Onrad plans provided superior homogeneity and D95 in head and neck cancer. The mean dose and V10-40 Gy of the parotid glands was lower using Onrad. In the cervical cancer plans, target doses were similar with both systems. Normal tissue doses were equal. CONCLUSIONS: Onrad is useful in the clinical setting. Onrad can achieve favorable or comparable dose distributions compared with those of 3DCRT in actual clinical treatment of breast, lung, prostate, head and neck, and cervical cancers.

Chemoradiotherapy for localized extranodal natural killer/T-cell lymphoma, nasal type, using a shrinking-field radiation strategy: multi-institutional experience.

PURPOSES: The prognosis of localized extranodal natural killer/T-cell lymphoma, nasal type (ENKTL), has improved with the development of chemoradiotherapy. However, conventional extended-field radiotherapy may cause optic disorders. Our group has employed smaller radiation fields in an attempt to avoid toxicity. The efficacy and toxicity of treatments were evaluated. MATERIALS AND METHODS: Chemoradiotherapy was delivered with a shrinking-field radiotherapy strategy. The endpoints of this study were overall survival (OS), local control (LC), progression-free survival (PFS), and toxicity. RESULTS: Fifteen patients with localized ENKTL were treated. After irradiation (median, 40 Gy) to the tumor plus a prophylactic volume, a reduced treatment volume to the tumor was boosted (median, 10 Gy). Twelve patients underwent chemoradiotherapy and 3 patients received radiotherapy alone. A complete response was achieved in 12 and a partial response in 3 patients. The 5-year OS, PFS, and LC rates were 80, 67, and 93 %, respectively. Distant recurrence occurred in 4 patients and locoregional and distant recurrence in 1 patient. Cataract (grade 3) and dry eye (grade 2) were observed as late adverse events in 1 patient each. CONCLUSIONS: Sufficiently high OS and LC were achieved with acceptable toxicities. Appropriate target volumes may be smaller with newer chemotherapy regimens.

Intensity modulated stereotactic body radiation therapy for single or multiple vertebral metastases with spinal cord compression.

PURPOSE: The purpose of this study was to evaluate the efficacy and toxicity of intensity modulated radiation therapy with simultaneous integrated boost (SIB-IMRT) for single or multiple vertebral metastases (VM) with spinal cord compression using tomotherapy. METHODS AND MATERIALS: Thirty patients with 40 VM were treated with SIB-IMRT as initial radiation therapy. Either 40 Gy in 8 fractions or 48 Gy in 16 fractions was prescribed depending on the Katagiri prognostic index. The radiation doses to the spinal cord and other risk organs were reduced to tolerance levels using intensity modulation. One to 4 lesions in consecutive vertebrae were treated in 1 course of SIB-IMRT. Radiologic and physical examinations were performed at 1-3 month intervals after SIB-IMRT. The Barthel index (BI) and numerical rating scale (NRS) were used to evaluate activities of daily living (ADL) and pain status, respectively. RESULTS: The median follow-up period was 8 months. The NRS significantly dropped at 1 month after SIB-IMRT (P < .0001) and the effect continued for over 2 months. No significant BI decrease was observed at 2 months after SIB-IMRT (P = .7). The 1-year local control rate was 84% (95% confidence interval, 70%-100%). No grade≥2 neurologic toxicity resulting from SIB-IMRT was observed. CONCLUSIONS: SIB-IMRT could be successfully applied to VM with spinal cord compression in up to 4 consecutive vertebrae. Good ADL preservation and pain control were achieved with acceptable toxicity.

Intensity-modulated radiation therapy using static ports of tomotherapy (TomoDirect): comparison with the TomoHelical mode.

PURPOSE: With the new mode of Tomotherapy, irradiation can be delivered using static ports of the TomoDirect mode. The purpose of this study was to evaluate the characteristics of TomoDirect plans compared to conventional TomoHelical plans. METHODS: TomoDirect and TomoHelical plans were compared in 46 patients with a prostate, thoracic wall or lung tumor. The mean target dose was used as the prescription dose. The minimum coverage dose of 95% of the target (D95%), conformity index (CI), uniformity index (UI), dose distribution in organs at risk and treatment time were evaluated. For TomoDirect, 2 to 5 static ports were used depending on the tumor location. RESULTS: For the prostate target volume, TomoDirect plans could not reduce the rectal dose and required a longer treatment time than TomoHelical. For the thoracic wall target volume, the V5Gy of the lung or liver was lower in TomoDirect than in TomoHelical (p = 0.02). For the lung target volume, TomoDirect yielded higher CI (p = 0.009) but smaller V5Gy of the lung (p = 0.005) than TomoHelical. Treatment time did not differ significantly between the thoracic wall and lung plans. CONCLUSION: Prostate cancers should be treated with the TomoHelical mode. Considering the risk of low-dose radiation to the lung, the TomoDirect mode could be an option for thoracic wall and lung tumors.

Radiotherapy for hilar or mediastinal lymph node metastases after definitive treatment with stereotactic body radiotherapy or surgery for stage I non-small cell lung cancer.

PURPOSE: Management of regional lymph node (LN) recurrence is an important issue in definitive treatment of non-small cell lung cancer (NSCLC). We evaluated clinical outcomes of conventional radiotherapy for hilar or mediastinal LN metastases developing after stereotactic body radiotherapy (SBRT) or surgery for stage I NSCLC. METHODS AND MATERIALS: Between 2004 and 2008, 26 patients with hilar or mediastinal LN metastases without local recurrence and distant metastasis after SBRT (n = 14) or surgery (n = 12) were treated with conventional radiotherapy. Twelve of the 14 post-SBRT patients (86%) were judged medically inoperable at the time of SBRT. All patients were treated to the hilum and mediastinum with conventional daily fractions of 2.0 Gy (n = 25) or 2.4 Gy (n = 1). The median total dose for treating metastatic LN was 60 Gy (range, 54-66 Gy) for the post-SBRT patients and 65 Gy (range, 60-66 Gy) for the post-surgery patients. Only 1 of the 14 post-SBRT patients and 8 of the 12 post-surgery patients received chemotherapy. RESULTS: For all 26 patients, the overall and cause-specific survival rates at 3 years from radiation for LN metastases were 36% and 51%, respectively (14% and 39%, respectively, for the 14 post-SBRT patients and both 64% for the 12 post-surgery patients). Three of the SBRT patients were alive at 35 to 43 months with (n = 2) or without (n = 1) further recurrence, and 4 of the post-surgery patients were alive at 36 to 62 months with (n = 2) or without (n = 2) further recurrence. The incidence of ≥grade 2 pulmonary toxicity was 49% at 1 year (53% for post-SBRT patients and 44% for post-surgery patients). A grade 5 pulmonary toxicity was observed in 1 of the post-SBRT patients. CONCLUSIONS: Conventional radiotherapy could successfully salvage LN relapses after SBRT as well as after surgery in 7 of 26 patients. Radiotherapy in this setting appears reasonably well tolerated.

Compatibility of the linear-quadratic formalism and biologically effective dose concept to high-dose-per-fraction irradiation in a murine tumor.

PURPOSE: To evaluate the compliance of linear-quadratic (LQ) model calculations in the high-dose range as used in stereotactic irradiation in a murine tumor model. METHODS AND MATERIALS: Female 10-week-old Balb/c mice bearing 1-cm-diameter EMT6 tumors in the hind legs were used. Single doses of 10-25 Gy were compared with 2-5 fractions of 4-13 Gy given at 4-hour intervals. Cell survival after irradiation was determined by an in vivo-in vitro assay. Using an α/ß ratio determined for in vitro EMT6 cells and the LQ formalism, equivalent single doses for the hypofractionated doses were calculated. They were then compared with actually measured equivalent single doses for the hypofractionated doses. These fractionation schedules were also compared simultaneously to investigate the concordance/divergence of dose-survival curves plotted against actual radiation doses and biologically effective doses (BED). RESULTS: Equivalent single doses for hypofractionated doses calculated from LQ formalism were lower than actually measured doses by 21%-31% in the 2- or 3-fraction experiments and by 27%-42% in the 4- or 5-fraction experiments. The differences were all significant. When a higher α/ß ratio was assumed, the discrepancy became smaller. In direct comparison of the 2- to 5-fraction schedules, respective dose-response curves almost overlapped when cell survival was plotted against actual radiation doses. However, the curves tended to shift downward by increasing the fraction number when cell survival was plotted against BED calculated using an α/ß ratio of 3.5 Gy for in vitro EMT6 cells. CONCLUSION: Conversion of hypofractionated radiation doses to single doses using the LQ formalism underestimated the in vivo effect of hypofractionated radiation by approximately 20%-40%. The discrepancy appeared to be larger than that seen in the previous in vitro study and tended to increase with the fraction number. BED appeared to be an unreliable measure of tumor response.

Non-invasive imaging of combretastatin activity in two tumor models: Association with invasive estimates.

INTRODUCTION: The efficacy of the vascular disrupting agent combretastatin A-4 phosphate (CA4P) depends on several factors including tumor size, nitric oxide level, interstitial fluid pressure, and vascular permeability. These factors vary among tumor types. The aim of this study was to investigate all these factors in two tumor models that respond differently to CA4P. MATERIAL AND METHODS: Mice bearing C3H mammary carcinomas or KHT sarcomas (200 to 800 mm(3)) were intraperitoneally injected with CA4P (100 mg/kg). Tumor size and the effect of a nitric oxide inhibitor nitro-L-arginine (NLA) administered intravenously were evaluated by necrotic fraction histologically assessed at 24 hours. Interstitial fluid pressure (IFP) was measured using the wick-in-needle technique, and vascular characteristics were assessed with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). RESULTS: Initial necrotic fraction was about 10% in both tumor models at 200 mm(3), but only increased significantly with tumor size in the C3H mammary carcinoma. In this tumor, CA4P significantly induced further necrosis by about 15% at all sizes, but in the KHT tumor, the induced necrotic fraction depended on tumor size. For both tumor types, NLA with CA4P significantly increased necrotic fraction above that for each drug alone. CA4P significantly decreased IFP in all tumors except in the 800 mm(3) C3H tumor, which had an initially non-significant lower value. Interstitial volume estimated by DCE-MRI increased in all groups, except the 800 mm(3) C3H tumors. DCE-MRI vascular parameters showed different initial characteristics and general significant reductions following CA4P treatment. CONCLUSIONS: Both tumor models showed differences in all factors before treatment, and in their response to CA4P. Perfusion and permeability as estimated by DCE-MRI play a central role in the CA4P response, and interstitial volume and IFP seemed related. These factors may be of clinical value in the planning of CA4P treatments.

Clinical outcomes of stereotactic body radiotherapy for stage I non-small cell lung cancer using different doses depending on tumor size.

BACKGROUND: The treatment schedules for stereotactic body radiotherapy (SBRT) for lung cancer vary from institution to institution. Several reports have indicated that stage IB patients had worse outcomes than stage IA patients when the same dose was used. We evaluated the clinical outcomes of SBRT for stage I non-small cell lung cancer (NSCLC) treated with different doses depending on tumor diameter. METHODS: Between February 2004 and November 2008, 124 patients with stage I NSCLC underwent SBRT. Total doses of 44, 48, and 52 Gy were administered for tumors with a longest diameter of less than 1.5 cm, 1.5-3 cm, and larger than 3 cm, respectively. All doses were given in 4 fractions. RESULTS: For all 124 patients, overall survival was 71%, cause-specific survival was 87%, progression-free survival was 60%, and local control was 80%, at 3 years. The 3-year overall survival was 79% for 85 stage IA patients treated with 48 Gy and 56% for 37 stage IB patients treated with 52 Gy (p = 0.05). At 3 years, cause-specific survival was 91% for the former group and 79% for the latter (p = 0.18), and progression-free survival was 62% versus 54% (p = 0.30). The 3-year local control rate was 81% versus 74% (p = 0.35). The cumulative incidence of grade 2 or 3 radiation pneumonitis was 11% in stage IA patients and 30% in stage IB patients (p = 0.02). CONCLUSIONS: There was no difference in local control between stage IA and IB tumors despite the difference in tumor size. The benefit of increasing the SBRT dose for larger tumors should be investigated further.

Estimation of errors associated with use of linear-quadratic formalism for evaluation of biologic equivalence between single and hypofractionated radiation doses: an in vitro study.

PURPOSE: To investigate the reliability of the linear-quadratic (LQ) formalism and the magnitude of errors associated with its use in assessing biologic equivalence between single, high radiation doses and hypofractionated radiation doses. METHODS AND MATERIALS: V79 and EMT6 single cells received single doses of 2-12 Gy or two or three fractions of 4 or 5 Gy, each at 4-h intervals. Single and fractionated doses to actually reduce the cell survival to the same level were determined by a colony assay. The alpha/beta ratio was obtained from the cell survival curves. Using the alpha/beta ratio and the LQ formalism, equivalent single doses for the hypofractionated doses were calculated. They were then compared with the actually determined equivalent single doses for the hypofractionated doses. The V79 spheroids received single doses of 5-26 Gy or two to five fractions of 5-12 Gy at 2 or 4-h interval, and then were assayed for cell survival. Next, equivalent single doses for the hypofractionated doses were determined, as were done for the single cells. RESULTS: The alpha/beta ratio was 5.1 Gy for the V79 single cells and 0.36 Gy for EMT6. In V79, the equivalent single doses for the hypofractionated doses calculated using the LQ formalism were 12-19% lower than the actually measured biologically equivalent single doses. In the EMT6 cells, this trend was also seen, but the differences were not significant. In the V79 spheroids, the calculated doses were 18-30% lower than the measured doses. CONCLUSION: Conversion of hypofractionated radiation doses to single doses using the LQ formalism could underestimate the effect of hypofractionated radiation by < or =30%.

Enhanced local tumour control after single or fractionated radiation treatment using the hypoxic cell radiosensitizer doranidazole.

OBJECTIVE: This study was designed to assess the potential of the nitroaromatic radiosensitizer doranidazole to preferentially enhance radiation-induced local control in a murine tumour. METHODS: A C3H mammary carcinoma grown in the right rear foot of female CDF1 mice was used and treated when at 200 mm(3) in size. Doranidazole was dissolved in saline and injected intravenously. Radiation (240 kV X-rays) was locally administered to the tumours or normal feet of restrained non-anaesthetised animals. Response endpoints were local tumour control at 90 days and moist desquamation in foot skin 11-23 days after irradiation. Following logit analysis of the radiation dose-response curves the TCD50 (tumour) or MDD50 (skin) doses (radiation doses producing a response in 50% of treated mice) were estimated and a sensitizer enhancement ratio (SER; ratio of the TCD50 or MDD50 for radiation alone and radiation with drug) calculated. Statistical analysis was performed using a chi(2) test (p<0.05). RESULTS: The TCD50 value (+/-95% confidence interval) for radiation alone as a single treatment was 53Gy (51-55). Injecting doranidazole (200 mg/kg) at 0, 30 or 60 min prior to irradiation significantly enhanced radiation response with the greatest effect seen at the 30-min interval [TCD50=40Gy (37-44); SER=1.3]. No enhancement occurred when the drug was given after radiation. Injecting different drug doses 30 min prior to irradiation showed a dose-response relationship; the respective SERs were 1.1, 1.3 and 1.8 at 50, 200 and 500 mg/kg. In skin, using the 200mg/kg dose and a 30-min interval, the SER was only 1.1. Combining doranidazole and radiation in a fractionated schedule gave a tumour SER of 1.1. CONCLUSIONS: Non-toxic doses of doranidazole significantly enhanced tumour response to single radiation treatments, an effect that was greater than that seen in a normal tissue. It also enhanced radiation given in a fractionated schedule. These effects were similar to those found with misonidazole and nimorazole, nitroaromatic radiosensitizers with clinical efficacy.

Preclinical studies to predict efficacy of vascular changes induced by combretastatin a-4 disodium phosphate in patients.

PURPOSE: To determine how combretastatin A-4 disodium phosphate (CA4DP) dose-dependent changes in radiation response of a C3H mouse mammary carcinoma relate to measurements of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) parameters and how those mouse DCE-MRI results compare with published clinical DCE-MRI data. METHODS AND MATERIALS: C3H mammary carcinomas grown in female CDF(1) mice were treated when at 200 mm(3) in size. Groups of mice were given graded radiation doses, either alone or followed 30 min later by an intraperitoneal injection of CA4DP, administered at doses of 10-250 mg/kg. The radiation dose producing local tumor control in 50% of treated animals at 90 days (TCD(50)) was calculated for each CA4DP dose. DCE-MRI was performed before and 3 h after CA4DP administration, and parameters describing vascularity and interstitial volume were estimated. RESULTS: TCD(50) showed a dose-dependent decrease reaching significance at 25 mg/kg. At greater doses of 50 and 100 mg/kg, the TCD(50) increased slightly and was not significantly different from that of controls. TCD(50) significantly decreased again at 250 mg/kg. The drug dose-response curves for all post-treatment vascular DCE-MRI parameters showed a shape similar to that of the TCD(50) curve. A similar dose dependency was seen with previously published clinical data. CONCLUSION: Our preclinical DCE-MRI data could predict the CA4DP enhancement of the tumor radiation response and suggest the clinical CA4DP doses necessary to improve the radiation response in patients.

Comparison of the biodistribution of two hypoxia markers [18F]FETNIM and [18F]FMISO in an experimental mammary carcinoma.

The first aim of this study was to compare the hypoxia imaging ability of fluorine-18 fluoroerythronitroimidazole ([18F]FETNIM) with that of fluorine-18 fluoromisonimidazole ([18F]FMISO) in murine tumours of different sizes under two different oxygenation conditions. Secondly, we wanted to assess the biodistribution of the markers in normal tissues under similar conditions. Female CDF1 mice with a C3H mammary carcinoma grown on their backs were used. Tumours were size matched and animals breathed either normal air (21% O(2)) or carbogen gas (95% O(2) + 5% CO(2)). The gassing procedure was begun 5 min before the intravenous injection of either [18F]FETNIM or [18F]FMISO and continued until the mice were sacrificed at 120 min. Blood, tumour, muscle, heart, lung, liver, kidney and fat were removed, counted for radioactivity and weighed. The tumour and muscle were frozen and cut with a cryomicrotome into sections. The spatial distribution of radioactivity from the tissue sections was determined with digital autoradiography. Estimation of the necrotic fraction was made on sections from formalin-fixed tumours. Digital autoradiography showed that the whole tumour-to-muscle radioactivity uptake ratios were significantly higher in normal air-breathing mice than in carbogen-treated mice for both [18F]FETNIM (4.9+/-2.6 vs 1.8+/-0.5; P<0.01) and [18F]FMISO (4.4+/-1.0 vs 1.5+/-0.4; P<0.01). The carbogen treatment had only slight effects on the biodistribution of either marker in normal tissues. The necrotic fraction determined in tumours did not correlate with the tumour volume or with the tumour-to-muscle radioactivity uptake ratio. This study shows that the uptake of both [18F]FETNIM and [18F]FMISO correlates with the oxygenation status in tumours. In addition, our data show no significant difference in the intratumoral uptake between the two markers. However, significantly higher radioactivity uptake values were measured for [18F]FMISO than for [18F]FETNIM in normal tissues.

Vascular targeting effects of ZD6126 in a C3H mouse mammary carcinoma and the enhancement of radiation response.

PURPOSE: The aim of this study was to investigate the pathophysiologic effects induced by the novel vascular targeting agent ZD6126 in a C3H mouse mammary carcinoma and to evaluate the agent's ability to inhibit tumor growth either when given alone or in combination with radiation. METHODS AND MATERIALS: A C3H mammary carcinoma grown in the right rear foot of female CDF1 mice was treated when at 200 mm(3) in size. ZD6126 was dissolved in saline and injected intraperitoneally. Blood perfusion was measured using the RbCl extraction procedure, tumor oxygen (pO(2)) status was assessed with the Eppendorf electrode, and tumor necrosis was estimated from histologic sections. Radiation (240-kV X-rays) was locally administered to tumors of restrained nonanesthetized mice, and response was assessed using a tumor growth assay. RESULTS: ZD6126 induced a significant dose- and time-dependent decrease in tumor perfusion, reaching a maximal 70% reduction around 3 h after injecting 150-300 mg/kg. However, full recovery was seen within 6 h. A 200 mg/kg dose significantly decreased tumor oxygenation status at 3 h (median pO(2) decreased from 7 to 3 mm Hg; % pO(2) values

Combination of vascular targeting agents with thermal or radiation therapy.

PURPOSE: The most likely clinical application of vascular targeting agents (VTAs) is in combination with more conventional therapies. In this study, we report on preclinical studies in which VTAs were combined with hyperthermia and/or radiation. METHODS AND MATERIALS: A C3H mammary carcinoma grown in the right rear foot of female CDF1 mice was treated when at 200 mm3 in size. The VTAs were combretastatin A-4 disodium phosphate (CA4DP, 25 mg/kg), flavone acetic acid (FAA, 150 mg/kg), and 5,6-dimethylxanthenone-4-acetic acid (DMXAA, 20 mg/kg), and were all injected i.p. Hyperthermia and radiation were locally administered to tumors of restrained, nonanesthetized mice, and response was assessed using either a tumor growth or tumor control assay. RESULTS: Heating tumors at 41.5 degrees C gave rise to a linear relationship between the heating time and tumor growth with a slope of 0.02. This slope was increased to 0.06, 0.09, and 0.08, respectively, by injecting the VTAs either 30 min (CA4DP), 3 h (FAA), or 6 h (DMXAA) before heating. The radiation dose (+/-95% confidence interval) that controls 50% of treated tumors (the TCD(50) value) was estimated to be 53 Gy (51-55 Gy) for radiation alone. This was decreased to 48 Gy (46-51 Gy), 45 Gy (41-49 Gy), and 42 Gy (39-45 Gy), respectively, by injecting CA4DP, DMXAA, or FAA 30-60 min after irradiating. These values were further decreased to around 28-33 Gy if the tumors of VTA-treated mice were also heated to 41.5 degrees C for 1 h, starting 4 h after irradiation, and this effect was much larger than the enhancement seen with either 41.5 degrees C or even 43 degrees C alone. CONCLUSIONS: Our preclinical studies and those of others clearly demonstrate that VTAs can enhance tumor response to hyperthermia and/or radiation and support the concept that such combination studies should be undertaken clinically for the full potential of VTAs to be realized.