Risk of radiation necrosis after hypofractionated stereotactic radiotherapy (HFSRT) for brain metastases: a single center retrospective study.

INTRODUCTION: While hypofractionated stereotactic radiotherapy (HFSRT) is being increasingly used for treating brain metastases, clinical data concerning the incidence and risk factors of its main side-effect, namely radiation necrosis (RN), remain limited. In this context, we assessed risk factors of RN in a single center series of patients with brain metastases treated with three common HFSRT dose regimens: 27 Gy in 3 fractions (27 Gy/3#), 30 Gy in 5 fractions (30 Gy/5#), and 35 Gy in 5 fractions (35 Gy/5#). METHODS: In total, 360 HFSRT treatments in 294 consecutive patients were retrospectively analysed. Univariable analysis (UVA) and multivariable analysis (MVA) were performed to evaluate the relationship between clinical and dosimetric factors and RN risk. RESULTS: The 12-month RN rate was 8.8%. On MVA, risk was higher in lesions receiving 27 Gy/3# (HR 3.07 95%CI [1.13;8.36], p = 0.03) and 35 Gy/5# (HR 4.22 95%CI [1.46,12.21], p < 0.01) than in lesions receiving 30 Gy/5#. Risk was also higher in patients having received immunotherapy within 3 months of HFSRT (HR 2.69 95%CI [1.10;6.56], p = 0.03) compared with those who did not. We found no association between RN risk and other tested factors, in particular prior irradiation, lesion histology, lesion location, lesion volume, or brain dosimetric factors. CONCLUSION: In the present series, HFSRT was associated with limited RN risk. Incidence of RN was higher with dose regimens delivering a higher biologically effective dose, as well as in patients having received immunotherapy within 3 months of HFSRT.

Influence of Linear Energy Transfer on the Nucleo-shuttling of the ATM Protein: A Novel Biological Interpretation Relevant for Particles and Radiation.

PURPOSE: Linear energy transfer (LET) plays an important role in radiation response. Recently, the radiation-induced nucleo-shuttling of ATM from cytoplasm to the nucleus was shown to be a major event of the radiation response that permits a normal DNA double-strand break (DSB) recognition and repair. Here, we aimed to verify the relevance of the ATM nucleo-shuttling model for high-LET particles and various radiation types. METHODS AND MATERIALS: ATM- and H2AX-immunofluorescence was used to assess the number of recognized and unrepaired DSB in quiescent fibroblast cell lines exposed to x-rays, γ-rays, 9- and 12-MeV electrons, 3- and 65-MeV protons and 75-MeV/u carbon ions. RESULTS: The rate of radiation-induced ATM nucleo-shuttling was found to be specific to each radiation type tested. By increasing the permeability of the nuclear membrane with statin and bisphosphonates, 2 fibroblast cell lines exposed to high-LET particles were shown to be protected by an accelerated ATM nucleo-shuttling. CONCLUSIONS: Our findings are in agreement with the conclusion that LET and the radiation/particle type influence the formation of ATM monomers in cytoplasm that are required for DSB recognition. A striking analogy was established between the DSB repair kinetics of radioresistant cells exposed to high-LET particles and that of several radiosensitive cells exposed to low-LET radiation. Our data show that the nucleo-shuttling of ATM provides crucial elements to predict radiation response in human quiescent cells, whatever the LET value and their radiosensitivity.

Influence of Nucleoshuttling of the ATM Protein in the Healthy Tissues Response to Radiation Therapy: Toward a Molecular Classification of Human Radiosensitivity.

PURPOSE: Whereas post-radiation therapy overreactions (OR) represent a clinical and societal issue, there is still no consensual radiobiological endpoint to predict clinical radiosensitivity. Since 2003, skin biopsy specimens have been collected from patients treated by radiation therapy against different tumor localizations and showing a wide range of OR. Here, we aimed to establish quantitative links between radiobiological factors and OR severity grades that would be relevant to radioresistant and genetic hyperradiosensitive cases. METHODS AND MATERIALS: Immunofluorescence experiments were performed on a collection of skin fibroblasts from 12 radioresistant, 5 hyperradiosensitive, and 100 OR patients irradiated at 2 Gy. The numbers of micronuclei, γH2AX, and pATM foci that reflect different steps of DNA double-strand breaks (DSB) recognition and repair were assessed from 10 minutes to 24 hours after irradiation and plotted against the severity grades established by the Common Terminology Criteria for Adverse Events and the Radiation Therapy Oncology Group. RESULTS: OR patients did not necessarily show a gross DSB repair defect but a systematic delay in the nucleoshuttling of the ATM protein required for complete DSB recognition. Among the radiobiological factors, the maximal number of pATM foci provided the best discrimination among OR patients and a significant correlation with each OR severity grade, independently of tumor localization and of the early or late nature of reactions. CONCLUSIONS: Our results are consistent with a general classification of human radiosensitivity based on 3 groups: radioresistance (group I); moderate radiosensitivity caused by delay of nucleoshuttling of ATM, which includes OR patients (group II); and hyperradiosensitivity caused by a gross DSB repair defect, which includes fatal cases (group III).

Practice patterns of photon and proton pediatric image guided radiation treatment: results from an International Pediatric Research consortium.

PURPOSE: Image guided radiation therapy (IGRT) has become common practice for both photon and proton radiation therapy, but there is little consensus regarding its application in the pediatric population. We evaluated clinical patterns of pediatric IGRT practice through an international pediatrics consortium comprised of institutions using either photon or proton radiation therapy. METHODS AND MATERIALS: Seven international institutions with dedicated pediatric expertise completed a 53-item survey evaluating patterns of IGRT use in definitive radiation therapy for patients ≤21 years old. Two institutions use proton therapy for children and all others use IG photon therapy. Descriptive statistics including frequencies of IGRT use and means and standard deviations for planning target volume (PTV) margins by institution and treatment site were calculated. RESULTS: Approximately 750 pediatric patients were treated annually across the 7 institutions. IGRT was used in tumors of the central nervous system (98%), abdomen or pelvis (73%), head and neck (100%), lung (83%), and liver (69%). Photon institutions used kV cone beam computed tomography and kV- and MV-based planar imaging for IGRT, and all proton institutions used kV-based planar imaging; 57% of photon institutions used a specialized pediatric protocol for IGRT that delivers lower dose than standard adult protocols. Immobilization techniques varied by treatment site and institution. IGRT was utilized daily in 45% and weekly in 35% of cases. The PTV margin with use of IGRT ranged from 2 cm to 1 cm across treatment sites and institution. CONCLUSIONS: Use of IGRT in children was prevalent at all consortium institutions. There was treatment site-specific variability in IGRT use and technique across institutions, although practices varied less at proton facilities. Despite use of IGRT, there was no consensus of optimum PTV margin by treatment site. Given the desire to restrict any additional radiation exposure in children to instances where the exposure is associated with measureable benefit, prospective studies are warranted to optimize IGRT protocols by modality and treatment site.

Permanent 125I-seed prostate brachytherapy: early prostate specific antigen value as a predictor of PSA bounce occurrence.

PURPOSE: To evaluate predictive factors for PSA bounce after 125I permanent seed prostate brachytherapy and identify criteria that distinguish between benign bounces and biochemical relapses. MATERIALS AND METHODS: Men treated with exclusive permanent 125I seed brachytherapy from November 1999, with at least a 36 months follow-up were included. Bounce was defined as an increase ≥ 0.2 ng/ml above the nadir, followed by a spontaneous return to the nadir. Biochemical failure (BF) was defined using the criteria of the Phoenix conference: nadir +2 ng/ml. RESULTS: 198 men were included. After a median follow-up of 63.9 months, 21 patients experienced a BF, and 35.9% had at least one bounce which occurred after a median period of 17 months after implantation (4-50). Bounce amplitude was 0.6 ng/ml (0.2-5.1), and duration was 13.6 months (4.0-44.9). In 12.5%, bounce magnitude exceeded the threshold defining BF. Age at the time of treatment and high PSA level assessed at 6 weeks were significantly correlated with bounce but not with BF. Bounce patients had a higher BF free survival than the others (100% versus 92%, p = 0,007). In case of PSA increase, PSA doubling time and velocity were not significantly different between bounce and BF patients. Bounces occurred significantly earlier than relapses and than nadir + 0.2 ng/ml in BF patients (17 vs 27.8 months, p < 0.0001). CONCLUSION: High PSA value assessed 6 weeks after brachytherapy and young age were significantly associated to a higher risk of bounces but not to BF. Long delays between brachytherapy and PSA increase are more indicative of BF.

GATA3 is a master regulator of the transcriptional response to low-dose ionizing radiation in human keratinocytes.

BACKGROUND: The general population is constantly exposed to low levels of radiation through natural, occupational or medical irradiation. Even if the biological effects of low-level radiation have been intensely debated and investigated, the molecular mechanisms underlying the cellular response to low doses remain largely unknown. RESULTS: The present study investigated the role of GATA3 protein in the control of the cellular and molecular response of human keratinocytes exposed to a 1 cGy dose of X-rays. Chromatin immunoprecipitation showed GATA3 to be able to bind the promoter of 4 genes responding to a 1 cGy exposure. To go further into the role of GATA3 after ionizing radiation exposure, we studied the cellular and molecular consequences of radiation in GATA3 knock-down cells. Knock-down was obtained by lentiviral-mediated expression of an shRNA targeting the GATA3 transcript in differentiated keratinocytes. First, radiosensitivity was assessed: the toxicity, in terms of immediate survival (with XTT test), associated with 1 cGy radiation was found to be increased in GATA3 knock-down cells. The impact of GATA3 knock-down on the transcriptome of X-ray irradiated cells was also investigated, using oligonucleotide microarrays to assess changes between 3 h and 72 h post-irradiation in normal vs GATA3 knock-down backgrounds; transcriptome response was found to be completely altered in GATA3 knock-down cells, with a strong induction/repression peak 48 h after irradiation. Functional annotation revealed enrichment in genes known to be involved in chaperone activity, TGFbeta signalling and stress response. CONCLUSION: Taken together, these data indicate that GATA3 is an important regulator of the cellular and molecular response of epidermal cells to very low doses of radiation.

Active breathing control for Hodgkin's disease in childhood and adolescence: feasibility, advantages, and limits.

PURPOSE: The challenge in early Hodgkin's disease (HD) in children is to maintain good survival rates while sparing organs at risk. This study assesses the feasibility of active breathing control (ABC) in children, and compares normal tissue irradiation with and without ABC. METHODS AND MATERIALS: Between May 2003 and June 2004, seven children with HD with mediastinal involvement, median age 15, were treated by chemotherapy and involved-field radiation therapy. A free-breathing computed tomography simulation scan and one additional scan during deep inspiration using ABC were performed. A comparison between planning treatment with clinical target volume including supraclavicular regions, mediastinum, and hila was performed, both in free breathing and using ABC. RESULTS: For a prescription of 36 Gy, pulmonary dose-volume histograms revealed a mean reduction in lung volume irradiated at more than 20 Gy (V20) and 30 Gy (V30) of 25% and 26%, respectively, using ABC (p = 0.016). The mean volume of heart irradiated at 30 Gy or more decreased from 15% to 12% (nonsignificant). The mean dose delivered to breasts in girls was small in both situations (less than 2 Gy) and stable with or without ABC. Considering axillary irradiation, the mean dose delivered to breasts remained low (<9 Gy), without significant difference using ABC or not. The mean radiation dose delivered to thyroid was stable using ABC or not. CONCLUSIONS: Using ABC is feasible in childhood. The use of ABC decreases normal lung tissue irradiation. Concerning heart irradiation, a minimal gain is also shown. No significant change has been demonstrated concerning breast and thyroid irradiation.

Exclusive brachytherapy for T1 and T2 squamous cell carcinomas of the velotonsillar area: results in 44 patients.

PURPOSE: To evaluate the role of interstitial brachytherapy as an exclusive radiotherapy modality for primary T1-T2 squamous cell carcinomas (SCC) of the velotonsillar area. METHODS AND MATERIALS: Between 1992 and 2000, 44 patients with T1-T2 SCC of the tonsil (n = 36) and soft palate (n = 8) were treated to the primary with brachytherapy alone (37 patients) or after a limited resection (7 patients). Eight patients had prior external beam radiation therapy (EBRT) for previous head-and-neck carcinoma. Nineteen patients had initial neck dissection. The mean brachytherapy dose was 58.7 Gy, and the mean reference dose rate and Ir-192 linear activity were 58.2 cGy/h and 1.51 mCi/cm respectively. RESULTS: With a 75-month median follow-up, 1 patient recurred locally. Isolated nodal relapses occurred in 4 patients, none of whom had initial neck dissection, and salvage therapy was successful in 2. Five-year overall and progression-free survival rates were 76% and 68%, respectively. Full-course radiation therapy was possible in 7 of 12 patients who developed a second primary head-and-neck carcinoma. Late toxicity was limited to 6 mild soft-tissue necroses, and was significantly associated with previous surgery to the primary and high linear activity. CONCLUSIONS: Exclusive brachytherapy for T1-T2 velotonsillar carcinomas is safe and effective, and permits definitive reirradiation for a second head-and-neck cancer. Initial neck dissection should be performed for optimal selection for exclusive brachytherapy.

Three-dimensional conformal radiotherapy for paranasal sinus carcinoma: clinical results for 25 patients.

PURPOSE: To assess local control, survival, and clinical and dosimetric prognostic factors in 25 patients with locally advanced maxillary or ethmoid sinus carcinoma treated by three-dimensional conformal radiotherapy (RT). MATERIALS AND METHODS: Surgery was performed in 22 patients and was macroscopically complete in 16. Seven patients received chemotherapy (concomitant with RT in four). The following quality indexes were defined for the 95% and 90% isodoses: tumor conformity index, normal tissue conformity index, and global conformity index. RESULTS: The median radiation dose to the planned treatment volume was 63 Gy, with a minimal dose of 60 Gy, except in 2 patients whose cancer progressed during RT. The maximal doses tolerated by the structures involved in vision were respected, except for tumors that involved the optic nerve. After a median follow-up of 25 months, 14 local tumor recurrences developed. The major prognostic factors were central nervous system involvement by disease and the presence of nonresectable tumors. The radiation dose and tumor conformity index value were not significant prognostic indicators. Two patients died of acute infectious toxicity, and two developed late ipsilateral ocular toxicity. CONCLUSIONS: Improving local control remains the main challenge in RT for paranasal tumors.

Patient setup error measurement using 3D intensity-based image registration techniques.

PURPOSE: Conformal radiotherapy requires accurate patient positioning with reference to the initial three-dimensional (3D) CT image. Patient setup is controlled by comparison with portal images acquired immediately before patient treatment. Several automatic methods have been proposed, generally based on segmentation procedures. However, portal images are of very low contrast, leading to segmentation inaccuracies. In this study, we propose an intensity-based (with no segmentation), fully automatic, 3D method, associating two portal images and a 3D CT scan to estimate patient setup. MATERIALS AND METHODS: Images of an anthropomorphic phantom were used. A CT scan of the pelvic area was first acquired, then the phantom was installed in seven positions. The process is a 3D optimization of a similarity measure in the space of rigid transformations. To avoid time-consuming digitally reconstructed radiograph generation at each iteration, we used two-dimensional transformations and two sets of specific and pregenerated digitally reconstructed radiographs. We also propose a technique for computing intensity-based similarity measures between several couples of images. A correlation coefficient, chi-square, mutual information, and correlation ratio were used. RESULTS: The best results were obtained with the correlation ratio. The median root mean square error was 2.0 mm for the seven positions tested and was, respectively, 3.6, 4.4, and 5.1 for correlation coefficient, chi-square, and mutual information. CONCLUSIONS: Full 3D analysis of setup errors is feasible without any segmentation step. It is fast and accurate and could therefore be used before each treatment session. The method presents three main advantages for clinical implementation-it is fully automatic, applicable to all tumor sites, and requires no additional device.