This study investigated the effect of combining radiation with an angiogenesis inhibitor and vascular disrupting agent on tumor response and systemic toxicity. CDF1 mice with 200 mm3 foot implanted C3H mammary carcinomas were treated with TNP-470 (100 mg/kg every second day for 2 weeks; s.c.) and combretastatin A-4 phosphate (CA4P; 1 × 250 mg/kg, i.p.). Radiation (230-kV X-rays) was locally administered to tumors of restrained non-anesthetized mice. Response was tumor growth delay and change in mouse body weight. Radiation induced changes in serum levels of 10 cytokines up to 72-h after irradiation were measured using a Luminex assay. The results showed that TNP-470 (100 mg/kg × 7) or CA4P (250 mg/kg × 1) significantly (Student’s t-test; p < 0.05) inhibited tumor growth; the greatest effect when these two drugs were combined. TNP-470 and CA4P, alone or together, also significantly enhanced tumor response to radiation. No systemic toxicity occurred with drugs administered alone or in combination, but toxicity was observed when TNP-470 was combined with radiation. Serum cytokine levels only showed a significant transient increase in IL-6 1-h after irradiating. In conclusion, combining different acting vascular targeting agents with radiation increased anti-tumor activity. However, this benefit may sometimes be associated with a radiation-induced inflammatory response increasing systemic toxicity.

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.

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.

Background and aim of the work: This study aims to evaluate the usefulness of the response to induction chemotherapy (IC) in selecting candidates for definitive concurrent chemoradiotherapy in oropharyngeal cancer. Methods: Thirty-nine patients with oropharyngeal cancer received IC followed by definitive chemoradiotherapy or radiotherapy. The predominant IC regimens involved cisplatin and 5-fluorouracil with or without docetaxel. Patients who responded to IC received definitive organ-preserving treatment. Surgery was considered for patients who did not respond to IC. Only patients who underwent definitive radiotherapy were analyzed in this study. The associations between clinical parameters and local control (LC) or overall survival (OS) were also analyzed. Results: The follow-up periods of the surviving patients ranged from 9-170 months (median, 40). The 5-year LC and OS rates for all 39 patients were 81% and 60%, respectively. The 5-year LC and OS rates of the IC responders, complete response or partial response (CR, PR) were 89% and 65%, respectively, whereas those of the non-responders, stable disease or progressive disease (SD, PD) were 34% and 38%, respectively. Multivariate analysis demonstrated that the response to IC (p=0.00) and T-category (T1, 2 vs. T3, 4) (p=0.03) were correlated with LC, but only the response to IC was correlated with OS (p=0.04). None of the patients suffered severe late complications. Conclusions: Chemoselection appears to aid the selection of optimal treatments for patients with oropharyngeal cancer.

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 13 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 b.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 VMwith spinal cord compression in up to 4 consecutive vertebrae. Good ADL preservation and pain controlwere achievedwith acceptable toxicity. (C) 2014 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.

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.

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.

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 alpha/beta 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 alpha/beta 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 alpha/beta 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. (C) 2011 Elsevier Inc.

Serum levels of a sialylated carbohydrate antigen KL-6, a marker for interstitial pneumonitis, were serially measured before and after stereotactic body radiotherapy (SBRT) for lung tumors. It was suggested that KL-6 levels before and after SBRT would help to predict the occurrence of >= Grade 2 radiation pneumonitis. (C) 2011 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 101 (2011) 267-270

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.

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.

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 EM76 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 <= 30%. (C) 2009 Elsevier Inc.

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 53 Gy (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 = 40 Gy (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 200 mg/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. (C) 2008 Elsevier Ireland Ltd. ALL rights reserved.

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 CDF1 mice were treated when at 200 mm a 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 (TCD50) 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: TCD50 showed a dose-dependent decrease reaching significance at 25 mg/kg. At greater doses of 50 and 100 mg/kg, the TCD50 increased slightly and was not significantly different from that of controls. TCD50 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 TCD50 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. (C) 2008 Elsevier Inc.

La tomografía por emisión de positrones/tomografía computarizada (PET/TC) con 68Ga-PSMA es una técnica de imagen no invasiva para el estudio del cáncer de próstata con incremento de la expresión del antígeno prostático específico de membrana (prostate-specific membrane antigen, PSMA). El PSMA es una proteína transmembrana presente en todos los tejidos prostáticos. El incremento de la expresión de PSMA está presente en varios tumores, aunque su concentración es más elevada en el cáncer de próstata. Casi todos los adenocarcinomas de próstata muestran expresión de PSMA en la mayoría de las lesiones, tanto primarias como metastásicas. Estudios inmunohistoquímicos han demostrado que la expresión de PSMA está incrementada en pacientes con tumores desdiferenciados, metastásicos u hormonorrefractarios. Más aún, el nivel de expresión del PSMA tiene un valor pronóstico para la evolución de la enfermedad. La tomografía por emisión de positrones proporciona una medida de la distribución tridimensional del 68Ga-PSMA, obteniendo imágenes semicuantitativas que permiten valorar de forma no invasiva la expresión de PSMA.Positron emission tomography/computed tomography (PET/CT) with 68Ga-PSMA is a non-invasive diagnostic technique to image prostate cancer with increased prostate-specific membrane antigen (PSMA) expression. PSMA is a transmembrane protein present in all prostatic tissues. Increased PSMA expression is seen in several malignancies, although prostate cancer is the tumour where it presents higher concentrations. Almost all prostate adenocarcinomas show PSMA expression in most of lesions, primary and metastatic. Immunohistochemistry has demonstrated that the expression of PSMA increases in patients with de-differentiated, metastatic or hormone-refractory tumours. Moreover, the expression level of PSMA has a prognostic value for disease outcome. PET measures the three-dimensional distribution of 68Ga-PSMA, producing semi-quantitative images that allow for non-invasive assessment of PSMA expression.

The effect of combining the vascular targeting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) with both radiation and hyperthermia treatments was investigated in a transplanted C3H mouse mammary carcinoma and a normal mouse tissue. Tumours were grown on the right rear foot of female CDF1 mice and treated when sized 200 mm3. The foot skin of non-tumour-bearing CDF1 mice was used to assess normal tissue damage. Radiation and hyperthermia were given locally to the tumour/skin of restrained non-anaesthetized animals. DMXAA (20 mg/kg) was dissolved in saline and injected intraperitoneally 1 h after irradiating and then heating started 3 h later. The endpoints were local tumour control within 90 days or the development of moist desquamation in skin between 11 and 23 days after treatment. The radiation dose (+/- 95% confidence intervals) producing local tumour control in 50% of treated animals was 53 (51-55) Gy for radiation alone. This value was significantly (Chi-squared test; p < 0.05) decreased to 47 (42-52) Gy by DMXAA and to 47 (44-51) Gy by heating (41.5 degrees C/60 min) 4 h after irradiation. Combining both DMXAA and heating further reduced this to 30 (26-35) Gy. When the heating temperature was decreased to 40.5 degrees C, the effect of the triple combination was decreased but was still significant compared with radiation + DMXAA or radiation + hyperthermia. However, this enhancement disappeared at 39.5 degrees C. Radiation damage of normal foot skin was not enhanced by combining DMXAA and hyperthermia at 41.5 degrees C. In conclusion, adding DMXAA to thermoradiotherapy at 40.5-41.5 degrees C significantly improved local tumour control without enhancing normal tissue damage. Thus, including a vascular targeting agent in a mild thermoradiotherapy treatment regimen is a useful approach that may lead to a re-evaluation of the use of hyperthermia in cancer treatment.