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Purpose: To test feasibility and safety of clinical usage of Flattening Filter Free (FFF) beams for delivering ablative stereotactic body radiation therapy (SBRT) doses to various tumor sites, by means of Varian TrueBeam™ (Varian Medical Systems). Methods and Materials: Seventy patients were treated with SBRT and FFF: 51 lesions were in the thorax (48 patients),10 in the liver, 9 in isolated abdominal lymph node, adrenal gland or pancreas. Doses ranged from 32 to 75 Gy, depending on the anatomical site and the volume of the lesion to irradiate. Lung lesions were treated with cumulative doses of 32 or 48 Gy, delivered in 4 consecutive fractions. The liver patients were treated in 3 fractions with total dose of 75 Gy. The isolated lymph nodes were irradiated in 6 fractions with doses of 45 Gy. The inclusion criteria were the presence of isolated node, or few lymph nodes in the same lymph node region, in absence of other active sites of cancer disease before the SBRT treatment. Results: All 70 patients completed the treatment. The minimum follow-up was 3 months. Six cases of acute toxicities were recorded (2 Grade2 and 2 Grade3 in lung and 2 Grade2 in abdomen). No patient experienced acute toxicity greater than Grade3. No other types or grades of toxicities were observed at clinical evaluation visits. Conclusions: This study showed that, with respect to acute toxicity, SBRT with FFF beams showed to be a feasible technique in 70 consecutive patients with various primary and metastatic lesions in the body. Keywords: Flattening Filter Free, SBRT, RapidArc, TrueBeam Introduction cancer (NSCLC). Highly focused doses of 60-66 in three In case of tumors at early stage, or in case of isolated fractions with SBRT to NSCLC in early stages, achieve small metastases, stereotactic body radiation therapy an actuarial 2-year local control of 95%. The position (SBRT) has proved to be a safe and feasible treatment of the lesion is a limitation in dose escalation: although approach, as demonstrated by the tumor response and less than 20% of patients showed high-grade toxicity, local control rates in selected series . toxicity greater than grade 3 were more frequent in Improvements in screening intensification and in patients with tumors proximal to the bronchial tree or management techniques have reached high levels of central chest region . In a retrospective review, Onishi accuracy so that it is possible to detect tumors at rather et al: analyzed a large number of SBRT treatments from early stages. The paradigm of the usefulness of SBRT in a Japanese multi-institutional database showing that localized primary tumors is early non small cell lung SBRT is safe and promising as a radical treatment for operable Stage I NSCLC . When the effective biologic dose was greater than 100 Gy, the survival rate was * Correspondence: firstname.lastname@example.org Radiotherapy and radiosurgery, Humanitas Cancer Center, Istituto Clinico higher. Humanitas, Rozzano (Milano), Italy Full list of author information is available at the end of the article © 2011 Scorsetti et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Scorsetti et al. Radiation Oncology 2011, 6:113 Page 2 of 8 http://www.ro-journal.com/content/6/1/113 Optimization of systemic cytotoxic chemotherapy total of 123 patients were treated with the TrueBeam™ schemes and tailored drugs are improving significantly newly installed. Seventy out of 123, were treated with survival of cancer patients. In this scenario, it is possible SBRT and FFF beams (SBRT-FFF group). In this group, to perform aggressive treatment of oligometastatic dis- 51 lesions were in the thorax (48 patients) and 19 in the ease with curative-intent . abdomen: 10 liver, 4 isolated abdominal lymphnode Promising studies, are exploring the safety and feasi- metastases, 3 adrenal gland, 2 pancreas. Table 1 sum- bility of SBRT in abdominal and pelvic sites [6-13]. marizes demographic data. Patients will be stratified Rusthoven showed that, in patients with metastatic liver into three groups: lung, abdominal and liver cases. lesions, it is possible to deliver safely 60 Gy, in three fractions . Protocols: inclusion criteria and dose prescription As a consequence, large groups of patients with primary Prescription doses ranged from 32 to 75 Gy (mean or metastatic lesions can deserve SBRT, as curative dose to target volume), depending on the site and on approach and improvements in precision and accuracy are the volume of the lesions. Good performance status advisable to allow safe prescription of more ablative doses. and good compliance to radiation treatment were Recently, two new technological platforms have been requested in all patients. Lung lesions (primary early made available to clinical practice. Firstly, Volumetric NSCLC and oligometastatic cases) were treated with Modulated Arc Therapy (VMAT) in its RapidArc format, cumulative doses of32or48Gy, delivered in 4 conse- allowed to reduce significantly the time needed to deliver cutive daily fractions. The dose of 32 Gy was pre- complex intensity modulated plans, allowing to treat hypo- scribed to lesions located centrally or at a distance < 2 fractionated regimes within few minutes [14-17]). Sec- cm from the carena and/or to lesion with maximum ondly, there has been increasing attention into the clinical diameter > 3 cm. In the remaining cases, a dose of 48 use of linear accelerators (LINAC) with photon beams Gy was prescribed. generated without usage of the flattening filter [18-24]. It The ten liver patients, were treated for metastatic seems possible to expect a reduction of out-of-field dose lesions in 3 fractions up to 75 Gy. Eligible patients met when flattening filter free (FFF) beams are used. This is these criteria: inoperable or medically unsuitable for mainly due to reduced head scatter and residual electron resection, maximum tumour diameter < 6 cm, one to contamination. FFF beams should therefore lead to three hepatic lesions. The 4 isolated lymph nodes, the reduced peripheral doses and patients may benefit by adrenal gland and pancreas cases were irradiated in 6 decreased exposure of normal tissue to scattered doses fractions up to 45 Gy. The inclusion criteria were the outside the field. Removal of the flattening filter implies presence of isolated or few lymph nodes in the same also the possibility to deliver treatments with higher dose rates, up to factor 4 at 10 MV, and with a much higher Table 1 Main characteristics of patients cohort dose per pulse. This, beside further improving time effi- Gender ciency for delivery, might have subsequent potential radio- Male 46 (66%) biology implications, now still unclear and deserving dedicated investigations. While research in the physics Female 24 (34%) domain for FFF beams is increasing, there are very few Age (y) clinical data where FFF beams are applied in clinical prac- Median 65 tice, particularly in SBRT treatments. Range 39-89 Over the last few years the clinical introduction of Primary site RapidArc in SBRT was explored and, to test the feasibil- Lung 34(48%) ity and safety of combining this technique with FFF Colon 10(14%) beams, a group of patients was treated with ablative Breast 2(3%) SBRT doses to various anatomical tumor sites, by means Pancreas 2 (3%) of the recently introduced Varian TrueBeam™ system Uterus 1 (1,5%) (Varian Medical Systems, Palo Alto, CA, USA) [15,16,24,25]. The evaluation of the role of FFF beams in Sarcoma 6 (9%) reducing involvement of organs at risk while preserving Stomach 3 (4, %) adequate target coverage is not aim of the present study. Prostate 1(1,5%) Liver 4(6%) Materials and methods Endometrial 1(1,5%) Population of study Melanoma 1(1,5%) This is a prospective study and it was approved by the Unknown 5 (7%) Institution. Between September and December 2010, a Scorsetti et al. Radiation Oncology 2011, 6:113 Page 3 of 8 http://www.ro-journal.com/content/6/1/113 lymph node region, in absence of other active sites of and monitoring control system differ from the preceding cancer disease. LINAC series as described in . CT scans for planning were acquired for all patients All patients were treated with RapidArc with 6 (11 positioned supine with their arms above the head and cases) or 10 MV (59 cases) FFF beams. Energy selection immobilized by means of a thermoplastic body mask was based on achievable plan quality. The maximum (including a styrofoam block for abdominal compression dose rate enabled for FFF beams was 1400 MU/min for to minimize internal organ motion in abdominal cases). 6 MV and 2400 MU/min for 10 MV . RapidArc Contrast free and Contrast-enhanced planning CT scans plans were individually designed using full or partial sin- were acquired in free breathing mode at 3 mm slice gle or multiple arcs chosen to obtain the best adherence thickness. to planning objectives for each patient. All dose distri- The clinical target volume (CTV) included macro- butions were computed with the Analytical Anisotropic scopic and microscopic disease on CT as well as on Algorithm (AAA, version 8.9 ) implemented in the PET if available. The planning target volume (PTV) was Eclipse planning system with a calculation grid resolu- generated by taking into account both the internal mar- tion of 2.5 mm. gin (IM) and the set-up margin (SM). IM depends on A feature of TrueBeam™, applied to all the patients in intra- and inter-fraction organ motion (expected to be the study, is the so-called ‘jaws tracking’ mode. In this not significant in a short course of radiation for retro- mode, the main jaws of the LINAC are dynamically peritoneal nodes adjacent to spine and large vessels moved by the control system to the minimum aperture while it may be relevant for lung, pancreatic and liver needed to cover target projection and to maximize tumours) [26-30]. Since SM was minimised by the cone- organs at risk sparing at each gantry projection. beam CT (CBCT) verification of set up variations, the Treatment was delivered in 3 to 6 consecutive work- overall standardised CTV-PTV margin was prescribed as ing days, with the patient on a 3-hour fast to avoid 6-15 mm in the cranial-caudal axis and 3-8 mm in the gross displacement of stomach and bowel. Treatment anterior-posterior and lateral axes. For 70% of the lung delivery included stereotactic frame localization and patients, 4 DCT retrospective scans were acquired for CBCT in the first session aiming at a preliminary iso- planning purpose and PTV was defined using smaller centre positioning while for following fractions, patient margins, i.e. 5 mm isotropic in all directions. set-up was realised by means of CBCT image guidance Planning objectives to target coverage aimed to cover with, eventually, on-line couch adjustment at each frac- PTV with 95% of the prescribed dose (reduced to 67% tion. Image matching was performed on bones and, for few liver metastases cases whenever it was impossi- when visible, on tumors and other soft tissue structures ble to respect dose constraints to organs at risk). The (e.g. main blood vessels). main organs at risk (OAR) considered, depending on the treatment site, were: lungs, oesophagus, spinal cord, Evaluation of dosimetric and technical data heart, kidneys, stomach, duodenum, small bowel and For each group of patients, technical parameters of liver. Stomach, duodenum and small bowel were con- delivery were scored in terms of number of arcs, total toured when appropriate. For OARs, plans were number of monitor units (MU), monitor units per Gy required to meet explicit objectives as follows: Spinal (MU/Gy), total beam on time. Dosimetric quality of cord: D <18 Gy(dose lowerthan18Gytot a treatments was measured from dose volume histogram 0.1 cm3 volume of 0.1 cm ); V < 35% for both kidneys (less (DVH) analysis. For PTV, the target coverage (mean, 15 Gy than 35% of the volume receiving 15 Gy), V <3% D ,D ,V ,V ,V ,V ), the homogeneity 36 Gy 1% 95% 67% 80% 95% 107% for stomach and small bowel, V <(totalliver (Standard Deviation) and the conformity for PTV 15 Gy 3 3 volume minus 700 cm , i.e. at least 700 cm of liver (CI ) were reported. CI was defined as the ratio 95% should receive less than 15 Gy) for liver. In addition between the volume of patient irradiated at 95% of the D < 30 Gy for stomach and small bowel was con- prescribed dose and the PTV volume . For OARs, 0.5 cm3 sidered as a secondary objective. For lungs V < 30%, the mean dose, the maximum dose (D )andappro- 5Gy xcm3 V < 12% V < 10%. For heart and for oesopha- priate values of V (volume receiving at least xGy) 10 Gy 20 Gy xGy gus no explicit planning objectives were applied. were scored. SBRT procedure Evaluation of clinical data TrueBeam™ is a new LINAC designed to deliver flat- Clinical evaluations were planned on first day of treat- tened, as well as flattening filter-free (FFF) photon ment, before SBRT-FFF session (visit 0); visit 1 during beams. In TrueBeam™, many key elements including the the course of the treatment; visit 2 at the end of the last waveguide system, carousel assembly, beam generation, session; visit 3 within 60-90 days from the end of the Scorsetti et al. Radiation Oncology 2011, 6:113 Page 4 of 8 http://www.ro-journal.com/content/6/1/113 treatment. Unscheduled visits could be performed if Table 4 summarizes the technical delivery parameters. necessary. Target coverage (D )and homogeneityweresimilar 95% Acute radiation induced toxicities were scored accord- to those of abdomen SBRT treatments, published by our ing to NCI Common Terminology Criteria for Adverse group, characterized by high degree of conformality and Events (CTCAE version 3.0) . modest target overdosage (V ). For OARs, it was 107% A first assessment of treatment outcome, although possible to respect planning objectives in most of the obviously very early, was performed at first and second cases, also in the case of ipsilateral lung with a mean follow up visits and will be reported in terms of degree dose smaller than 5 Gy and V < 30%. 5Gy of response. Analysis of the technical delivery parameters showed that the availability of extended dose rate with FFF Results beams was fully exploited by the RapidArc technique Dosimetric and technical data with an average DR of 1500 and range spanning from Figure 1 illustrates examples of dose distributions of about 300 MU/min to a maximum of 2400 MU/min lung, abdominal and liver patients with display of an (leading to a relatively wide range of MU/deg from axial, sagittal and coronal plane. Figure 2 present aver- about 1 to about 17). As a consequence, although the age cumulative dose volume histograms for PTV and all dose per fraction reached 25 Gy, the beam on time, was organs at risk for the entire cohort of patients and for kept very small with a range from < 1 min to 5 min. the three sub groups. Table 2 shows results from DVH analysis for target Clinical Data volumes, stratified according to localization. Table 3 All 70 SBRT-FFF patients completed the treatment, as contains the results for OARs. programmed. The minimum follow-up was 3 months. Figure 1 Examples of dose distributions for the three groups of patients. Colourwash scale is from 20 to 50 Gy for the lung and the abdominal cases and from 35 to 80 Gy for the liver case. Scorsetti et al. Radiation Oncology 2011, 6:113 Page 5 of 8 http://www.ro-journal.com/content/6/1/113 Figure 2 Average cumulative DVH for OARs and PTV for all patients and stratified in the three groups. Six cases of acute toxicities were recorded (2 Grade 2 In 55 out of 70, early clinical outcome was assessable and 2 Grade 3 in lung and 2 Grade 2 in abdomen). No at first diagnostic evaluation with PET and/or CT: com- plete response was achieved in 10 patients, partial patient experienced acute toxicity greater than Grade 3. No other types or grades of toxicities were experienced response was in 26, and in 13 disease remained stable. at clinical evaluations. Progression was found in 6 irradiated lesions. Table 2 Summary of dose volume histogram analysis for PTV and healthy tissue Parameter All Lung Liver Abdomen PTV Volume [cm ] 78 ± 78 55 ± 55 146 ± 116 115 ± 82 Mean dose [%] 101.0 ± 2.9 101.2 ± 1.0 100.6 ± 1.6 100.3 ± 0.5 St. Dev. [%] 2.7 ± 0.6 2.9 ± 0.5 2.3 ± 0.8 2.1 ± 0.6 D [%] 106.0 ± 1.8 106.8 ± 1.5 104.3 ± 1.6 104.4 ± 1.4 1% D [%] 96.2 ± 1.0 96.1 ± 0.9 96.2 ± 1.5 96.4 ± 0.8 95% V [%] 97.3 ± 1.9 97.1 ± 1.7 97.2 ± 3.0 97.9 ± 1.5 95% V [%] 1.5 ± 5.1 2.1 ± 6.0 0.1 ± 0.2 0.0 ± 0.1 Healthy tissue Volume [cm ] 30660 ± 8928 29283 ± 7493 36232 ± 13301 31510 ± 8805 Mean [Gy] 1.2 ± 0.7 1.1 ± 0.8 1.4 ± 0.3 1.3 ± 0.6 V [%] 3.3 ± 2.7 3.0 ± 3.0 4.0 ± 1.3 3.9 ± 2.4 10 Gy CI 1.2 ± 0.3 1.3 ± 0.3 1.2 ± 0.3 1.2 ± 0.3 95% 3 4 Dose Int. [Gy*cm *10 ] 3.5 ± 2.1 3.1 ± 2.0 5.0 ± 2.1 4.1 ± 1.8 V : volume receiving at least × Gy. D : dose received by at least x% of the volume. CI: Conformity Index xGy x% Scorsetti et al. Radiation Oncology 2011, 6:113 Page 6 of 8 http://www.ro-journal.com/content/6/1/113 Table 3 Summary of dose volume histogram analysis for Table 3 Summary of dose volume histogram analysis for organs at risk organs at risk (Continued) Parameter All Lung Liver Abdomen Heart Ipsilateral Lung Volume 624 ± 190 629 ± 174 676 ± 298 365 ± 0.0 [cm ] Volume 1814.5 ± 1861.9 ± 1686.4 ± 1407.2 ± [cm ] 619.0 610.5 797.2 76.1 Mean [Gy] 4.3 ± 4.0 4.5 ± 4.2 4.3 ± 3.3 0.9 ± -0.0 Mean [Gy] 4.4 ± 3.0 4.9 ± 2.8 3.1 ± 3.1 0.2 ± 0.0 D [Gy] 15.3 ± 9.6 15.9 ± 9.7 14.9 ± 10.7 6.1 ± -0.0 1% V [%] 24.6 ± 18.3 27.6 ± 17.6 16.1 ± 17.0 0.0 ± 0.0 5Gy Oesophagus V [%] 15.5 ± 12.6 17.4 ± 12.3 9.5 ± 11.8 0.0 ± 0.0 10 Gy Volume 39 ± 43 32 ± 34 91 ± 86 - [cm ] V [%] 5.8 ± 4.8 6.6 ± 4.6 3.3 ± 5.4 0.0 ± 0.0 20 Gy Mean [Gy] 3.8 ± 2.9 3.8 ± 3.0 3.3 ± 3.7 - Contralateral Lung D [Gy] 13.6 ± 7.9 13.9 ± 8.0 10.8 ± 10.2 - Volume 1703 ± 629 1774 ± 615 1352 ± 765 1484 ± 335 1% [cm ] V : volume receiving at least × Gy. D : dose received by at least x% of the xGy x% volume. Mean [Gy] 1.6 ± 2.1 1.8 ± 2.2 1.0 ± 0.6 0.2 ± 0.1 V [%] 7.0 ± 14.3 8.0 ± 15.7 3.8 ± 3.5 0.0 ± 0.1 5Gy Discussion V [%] 2.7 ± 8.3 3.2 ± 9.2 0.1 ± 0.3 0.0 ± 0.0 10 Gy In the current study we report on the treatment of a V [%] 0.9 ± 2.9 1.1 ± 3.2 0.0 ± 0.0 0.0 ± 0.0 20 Gy group of patients undergoing SBRT with RapidArc Spinal cord technique in combination with flattening filter free Volume 65 ± 35 61 ± 36 76 ± 33 78 ± 28 photon beams with the new TrueBeam™ LINAC. The [cm ] rationale of the use of FFF beams for delivering SBRT D 9.9 ± 5.5 10.2 ± 6.1 9.4 ± 3.1 8.8 ± 4.9 0.1 cm3 doses, is the potential possibility to deliver high ablative [Gy] doses faster and more precisely, due to decreased out- D [Gy] 9.0 ± 4.5 9.1 ± 4.8 8.8 ± 3.2 8.4 ± 4.8 1% of-field dose and to increased dose rate removing flat- Liver tening filter . In addition, the time factor linked to Volume 1473 ± 409 1735 ± 606 1546 ± 434 1266 ± 193 the very high dose rates available, suggests that FFF [cm ] beams might be of interest also in the case of respira- Mean [Gy] 8.0 ± 5.8 3.2 ± 2.6 12.9 ± 3.7 3.8 ± 3.6 tory gated treatments where the trade-off of low duty V [%] 18.8 ± 17.1 3.2 ± 2.2 33.7 ± 10.7 6.2 ± 8.9 15 Gy cycle might be efficiently compensated. Another possible Ipsilateral Kidney and relatively obvious immediate advantage of high dose Volume 137 ± 38 - 134 ± 42 141 ± 38 rate of FFF beams is linked to the potential reduction of [cm ] intra-fraction motion, due to the reduction of total ses- Mean 5.0 ± 5.3 - 2.5 ± 2.4 7.8 ± 6.5 sion treatment time. All these aspects were not directly V [%] 11.5 ± 20.0 - 2.2 ± 3.6 22.4 ± 26.0 15 Gy addressed in the present study. The present study was Contralateral kidney limited to a more primordial aim: the demonstration of Volume 139 ± 35 - 126 ± 37 151 ± 30 the clinical feasibility of SBRT treatments with FFF [cm ] beams, the demonstration of short term safety of these Mean [Gy] 2.7 ± 2.1 - 2.0 ± 1.1 3.4 ± 2.7 V [%] 0.2 ± 0.7 - 0.0 ± 0.0 0.4 ± 1.0 15 Gy Stomach Table 4 Main Technical features of delivered treatments Volume 104 ± 40 - 104 ± 40 - Mean ± SD Range [cm ] MU 2780 ± 1493 [629÷6734] Mean [Gy] 7.3 ± 2.8 - 7.3 ± 2.8 - MU/Gy 283.6 ± 79.7 [164.1÷551.5] V [%] 0.0 ± 0.0 - 0.0 ± 0.0 - 36 Gy MU/arc 1955 ± 1312 [315÷6099] D 20.6 ± 3.6 - 20.6 ± 3.6 - 0.5 cm3 MU/deg 7.6 ± 4.3 [1.1÷17.2] [Gy] DR [MU/min] 1541 ± 621 [327÷2400] Small Bowell Gantry speed [deg/s] 4.4 ± 1.6 [1.4÷6.0] Volume 1255 ± 569 - - 1255 ± 569 CP aperture [cm] 1.7 ± 0.8 [0.2÷4.4] [cm ] CP area [cm ] 14.5 ± 10.4 [3.6÷55.2] Mean [Gy] 4.1 ± 4.4 - - 4.1 ± 4.4 Arc length [deg] 258.5 ± 70.5 [158÷358] V [%] 0.0 ± 0.0 - - 0.0 ± 0.0 36 Gy Beam on time [min] 1.7 ± 0.7 [0.9÷4.4] D 24.3 ± 13.0 - - 24.3 ± 13.0 0.5 cm3 See Additional figure 1 and 2 [Gy] Values are reported as averages over all patients, arcs and/or control points Scorsetti et al. Radiation Oncology 2011, 6:113 Page 7 of 8 http://www.ro-journal.com/content/6/1/113 (in terms of acute toxicity) and the investigation of dosi- it is necessary to assess definitive late toxicity and defi- metric and technical features of the treatments. nitive tumor control outcome. The objectives of this study were to evaluate feasibility and safety of SBRT with FFF beams. Although, in hypo- Author details fractionated treatments performed the most significant Radiotherapy and radiosurgery, Humanitas Cancer Center, Istituto Clinico expected complications are usually the late effects, it is Humanitas, Rozzano (Milano), Italy. Oncology Institute of Southern Switzerland, Bellinzona, Switzerland. remarkable that acute toxicity recorded in our popula- tion of study was mild, confirming the feasibility and Authors’ contributions safety of the clinical use of FFF beams in SBRT patients, MA, FA, AF, PM, LC, PN carried out the data, participated in the data evaluation and drafted the manuscript. MA, FA and LC participated in the which are the end points of the current evaluation in design of the study and PM and LC performed the statistical analysis. SC, the study. AC, FL, VP,CP, SP, GR, SA, AT, AA carried out the patients record evaluation It is established that late effects are frequently related and followed patients and treatments. The definitive supervision of the paper was done by MA and LC. All authors read and approved the final to the intensity of acute toxicity and based only on this manuscript. statement we can expect promising long term tolerabil- ity. On the other hand we have to consider that late Competing interests Luca Cozzi is Head of Research at Oncology Institute of Southern effects are mainly vascular mediate while the acute ones Switzerland and acts as Scientific Advisor to Varian Medical Systems. The are due to mitotic dead of replicating cells and the late authors Marta Scorsetti, Filippo Alongi, Simona Castiglioni, Alessandro Clivio, damage can also happen in absence of acute side effects. Antonella Fogliata, Francesca Lobefalo, Pietro Mancosu, Pierina Navarria, Valentina Palumbo, Chiara Pellegrini, Sara Pentimalli, Giacomo Reggiori, Anna Thus, a prolonged follow-up is needed to assess a good M Ascolese, Antonella Roggio, Stefano Arcangeli, Angelo Tozzi and Eugenio long term tolerability of the treatment and it will be the Vanetti declare that they have no competing interests. objective of our future analysis. 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Radiation Oncology 2011 6:113. • Thorough peer review • No space constraints or color ﬁgure charges • Immediate publication on acceptance • Inclusion in PubMed, CAS, Scopus and Google Scholar • Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit
Radiation Oncology – Springer Journals
Published: Sep 12, 2011
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