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Purpose: To determine the maximum tolerated dose (MTD) of fractionated intensity-modulated radiotherapy (IMRT) with temozolomide (TMZ) in patients with glioblastoma. Methods and Materials: A Phase I clinical trial was performed. Eligible patients had surgically resected or biopsy-proven glioblastoma. Patients started TMZ (75 mg/day) during IMRT and continued for 1 year (150–200 mg/day, Days 1–5 every 28 days) or until disease progression. Clinical target volume 1 (CTV1) was the tumor bed ± enhancing lesion with a 10-mm margin; CTV2 was the area of perifocal edema with a 20-mm margin. Planning target volume 1 (PTV1) and PTV2 were defined as the corresponding CTV plus a 5-mm margin. IMRT was delivered in 25 fractions over 5 weeks. Only the dose for PTV1 was escalated (planned dose escalation: 60 Gy, 62.5 Gy, 65 Gy) while maintaining the dose for PTV2 (45 Gy, 1.8 Gy/fraction). Dose limiting toxicities (DLT) were defined as any treatment-related nonhematological adverse effects rated as Grade ≥3 or any hematological toxicity rated as ≥4 by Radiation Therapy Oncology Group (RTOG) criteria. Results: Nineteen consecutive glioblastoma were treated with step-and-shoot IMRT, planned with the inverse approach (dose to the PTV1: 7 patients, 60 Gy; 6 patients, 62.5 Gy; 6 patients, 65 Gy). Five coplanar beams were used to cover at least 95% of the target volume with the 95% isodose line. Median follow-up time was 23 months (range, 8–40 months). No patient experienced DLT. Grade 1–2 treatment-related neurologic and skin toxicity were common (11 and 19 patients, respectively). No Grade >2 late neurologic toxicities were noted. Conclusion: Accelerated IMRT to a dose of 65 Gy in 25 fractions is well tolerated with TMZ at a daily dose of 75 mg. [Copyright &y& Elsevier]

Purpose: To determine lung dosimetric constraints that correlate with radiation pneumonitis in non–small-cell lung cancer patients treated with three-dimensional radiation therapy and concurrent chemotherapy. Methods and Materials: Between June 2002 and December 2006, 97 patients with locally advanced non–small-cell lung cancer were treated with concomitant radiochemotherapy. All patients underwent complete three-dimensional treatment planning (including dose-volume histograms), and patients were treated only if the percentage of total lung volume exceeding 20 Gy (V20) and 30 Gy (V30), and mean lung dose (MLD) had not exceeded the constraints of 31%, 18%, and 20 Gy, respectively. The total and ipsilateral lung dose–volume histogram parameters, planning target volume, and total dose delivered were analyzed and correlated with pneumonitis incidence. Results: If dose constraints to the total lung were respected, the most statistically significant factors predicting pneumonitis were the percentage of ipsilateral lung volume exceeding 20 Gy (V20ipsi), percentage of ipsilateral lung volume exceeding 30 Gy (V30ipsi), and planning target volume. These parameters divided the patients into low- and high-risk groups: if V20ipsi was 52% or lower, the risk of pneumonitis was 9%, and if V20ipsi was greater than 52%, the risk of pneumonitis was 46%; if V30ipsi was 39% or lower, the risk of pneumonitis was 8%, and if V30ipsi was greater than 39%, the risk of pneumonitis was 38%. Actuarial curves of the development of pneumonitis of Grade 2 or higher stratified by V20ipsi and V30ipsi were created. Conclusions: The correlation between pneumonitis and dosimetric constraints has been validated. Adding V20ipsi and V30ipsi to the classical total lung constraints could reduce pulmonary toxicity in concurrent chemoradiation treatment. V20ipsi and V30ipsi are important if the V20 to the total lung, V30 to the total lung, and mean lung dose have not exceeded the constraints of 31%, 18%, and 20 Gy, respectively. [Copyright &y& Elsevier]

In-vivo dosimetry (IVD) in external beam radiotherapy is used to detect major clinically relevant differences between planned and delivered dose. Moreover, a detailed analysis of its results, when routinely reported and discussed by the radiotherapy staff, can limit the likelihood of error transmission to many treatments. A first experience of routine EPID-based IVD in a reference point has been performed in our department for 3D-CRT treatments over a three-year period. More than 14,000 images were acquired and 1287 treatment plans were verified. The IVD checks were obtained three times in the first week and then weekly. Tolerance levels of ± 5% for pelvic-abdomen, head-neck and breast irradiations and ± 6% for lung treatments were adopted for the in-vivo measured dose per fraction. A statistical analysis of the IVD results was performed grouping the data by: anatomical regions, treatment units, open and wedged fields and gantry angles. About 10% of the checked doses per fraction showed dosimetric discrepancies out of the tolerance levels. The causes of the discrepancies were 70% delivery or planning errors, 20% morphological changes and 10% procedural limitations. 41 cases (3.2%) have required special investigations because their in-vivo doses per fraction, averaged over the first three sessions, were out of the tolerance levels and in 19 cases (1.5%) the deviations gave rise to an intervention. Statistically significant differences of average variations between planned and delivered doses were observed for: (i) 30° wedged 10 MV fields with respect to those of other wedged or open 10 MV fields delivered by two linacs, due to the incorrect TPS implementation of that wedge transmission factor; (ii) anterior-posterior and posterior-anterior beams with respect to the other gantry orientations for one linac, due to the beam attenuation introduced by the treatment couch; (iii) lateral fields with respect to medial fields of breast irradiations for all linacs, due to small systematic set-up variations. The analysis of our data shows a substantial homogeneity of the IVD results for all the considered body regions and treatment units. However, the observed discrepancies have supplied indications for taking further steps in the optimization process and in some cases to adopt an adaptive approach.

Aim: To report the acute toxicity of a hypofractionated regimen of intensity-modulated radiotherapy with simultaneous integrated boost (SIB-IMRT) to the pelvic nodes and the prostatic bed after radical prostatectomy., Patients and Methods: Patients with prostate adenocarcinoma at high risk of relapse after radical prostatectomy or with biochemical relapse were deemed eligible for study. SIB-IMRT was prescribed to the whole pelvis (45-Gy delivered in 1.8-Gy fractions) and the prostatic bed [62.5 Gy, 2.5-Gy fractions, Equivalent Dose in 2-Gy fraction (EQD2)=68.75 Gy, α/β=3]. Acute toxicity was recorded and graded according to Radiation Therapy Oncology Group (RTOG) criteria., Results: Forty-nine patients were enrolled. No cases of grade ≥ 3 acute toxicity were recorded. Grade 2 acute genitourinary and gastrointestinal toxicity was observed in 9.6% and 29.7% of patients, respectively., Conclusion: After radical prostatectomy, hypofractionated high-dose SIB-IMRT enables for reduction of the overall treatment time, with an acute toxicity profile which compares favourably with that of conventionally fractionated high-dose three-dimensional conformal radiotherapy (3D-CRT).

The transit in vivo dosimetry performed by an electronic portal imaging device (EPID) is a very practical method to check error sources in radiotherapy. Recently, the present authors have developed an in vivo dosimetry method based on correlation functions, F (w, L), defined as the ratio between the transit signal, S(t) (w, L), by the EPID and the mid-plane dose, D(m) (w, L), in a solid water phantom as a function of the phantom thickness, w, and of the field dimensions, L. In particular, generalized correlation functions F (w, L) for 6, 10 and 15 MV X-ray beams supplied by a pilot Varian linac, are here used by other three linacs operating in two centers. This way the workload, due to measurements in solid water phantom, needed to implement the in vivo dosimetry method was avoided. This article reports a feasibility study on the potentiality of this procedure for the adaptive radiotherapy of lung tumors treated by 3D conformal radiotherapy techniques. In particular, the dose reconstruction at the isocenter point D(iso) in the lung tumor has been used as dose-guided radiotherapy (DGRT), to detect the inter-fraction tumor anatomy variations that can require new CT scans and an adaptive plan. When a difference greater than 6% between the predicted dose by the treatment planning system (TPS), D (iso,TPS) and the D(iso) was observed, the clinical action started to detect possible anatomical lung tumor changes. Twelve over twenty patients examined presented in vivo dose discrepancies due to the tumor morphological changes during treatments, and these results were successively confirmed by new CT scans. In this work, for a patient that showed for all beams, D (iso) values over the tolerance level, the new CT scan was used for an adaptive plan. The lung dose volume histogram for D (iso,TPS) = 2 Gy per fraction suggested the adaptive plan. In particular, the lung volume included in 2 Gy increased from 350 cm(3) of the original plan to 550 cm(3) of the hybrid plan, while for the adaptive plan the lung volume included in 2 Gy decreased to 15 cm(3). Moreover, the mean doses to the organs at risk were reduced to 70%. The results of this research show that the DGRT procedure by the D(iso) reconstruction, integrated with radiological imaging, was feasible for periodic investigation on morphological lung tumor changes. This feasibility study takes into account the accuracy of two algorithms based on the pencil beam and collapsed cone convolution models for dose calculations where large density inhomogeneities are present.

Scarce data are available on the use of extracranial stereotactic radiotherapy in recurrent gynecological tumors. The aim of this report was to analyze the results of our preliminary experience with extracranial stereotactic radiotherapy in locally or distantly recurrent gynecological tumors. Extracranial stereotactic radiotherapy was planned by the Precise-Plan treatment planning system. Patients were immobilized using the Stereotactic Body-Frame. Five consecutive daily fractions were delivered; dose/fraction and total dose were defined based on an institutional dose-escalation protocol. A class solution with 4 non-coplanar fixed beams based on the tetrad configuration was used in all patients. Eleven patients (12 lesions), were included in the analysis. Stereotactic radiotherapy was delivered as first radiotherapy treatment (5 patients), or as retreatment (6 patients). Complete clinical response was achieved in 8/12 lesions (66.6%), while partial response was documented in 2/12 lesions (16.6%). With a median follow-up of 19 months (range, 2-37 months), 7 patients (63%) experienced local and/or distant progression of disease. The 2-year local progression-free survival was 81.8%, while the 2-year metastases-free survival was 54.4%. The 2-year overall survival was 63.6%. Acute and late toxicities were grade 2 or less. There was no difference in quality of life scores between the data collected before extracranial stereotactic radiotherapy and at first follow-up evaluation. Fractionated extracranial stereotactic radiotherapy administered up to a dose of 30 Gy in five fractions is well tolerated. Further studies of extracranial stereotactic radiotherapy and novel radiotherapy techniques are warranted in the challenging setting of recurrent gynecological tumors.

An amorphous silicon (a-Si) electronic portal imaging device (EPID) was implemented to perform transit in vivo dosimetry for dynamic conformal arc therapy (DCAT). A set of images was acquired for each arc irradiation using the EPID cine acquisition mode, that supplies a frame acquisition rate of one image every 1.66 s, with a monitor unit rate equal to 100 UM/min. In these conditions good signal stability, +/-1% (2SD) evaluated during 3 months, signal reproducibility within +/-0.8% (2SD) and linearity with dose and dose rate within +/-1% (2SD) were obtained. The transit signal, S (t), due to the transmitted radiotherapy beam below a solid phantom, measured by the EPID cine acquisition mode was used to determine, (1) a set of correlation functions, F(w, L), defined as the ratio between S (t) and the dose at half thickness, D (m), measured in solid water phantoms of different thicknesses, w and with square fields of side L, (2) a set of factors, f(d, L), that take into account the different x-ray scatter contribution from the phantom to the S (t) signal as a function of the variation, d, of the air gap between the phantom and the EPID. The reconstruction of the isocenter dose, D (iso), for DCAT was obtained convolving the transit signal values, obtained at different gantry angles, with the respective reconstruction factors determined by a house-made software. The method was applied to a first patient and the results show that the reconstructed D (iso) values can be obtained with an accuracy within +/-5%. In conclusion, it was assessed that an a-Si EPID with the cine acquisition mode is suitable to perform transit in vivo dosimetry for the DCAT therapy.

Background and Purpose: To evaluate the results in terms of dosimetric parameters and acute toxicity of two clinical studies (MARA-1 and MARA-2) on accelerated IMRT-based postoperative radiotherapy. These results are compared with historical control group (CG) of patients treated with "standard" 3D postoperative radiotherapy., Materials and Methods: Prescribed dose to the breast was 50.4Gy in the CG, 40Gy in MARA-1 (low risk of local recurrence), and 50Gy in MARA-2 (medium-high risk of recurrence). The tumor bed total dose was 60.4Gy (sequential 10Gy electron boost), 44Gy (concomitant 4Gy boost), and 60Gy (concomitant 10Gy boost) in CG, MARA-1 and MARA-2 studies, respectively. Overall treatment time was of 32 fractions for CG (6.4weeks); 16 fractions for MARA-1 study (3.2weeks) and 25 fractions for MARA-2 study (5weeks)., Results: Three hundred and thirty two patients were included in the analysis. Dosimetric analysis showed D(max) and V(107%) reduction (p<0.001) and D(min) improvement (p<0.001) in the PTV in patients treated with IMRT. Grade 2 acute skin toxicity was 33.6%, 13.1%, and 45.1% in the CG, MARA-1, and MARA-2, respectively (p<0.001), and grade 3 acute skin toxicity was 3.1%, 1.0%, and 2.0%, respectively. Similarly, larger PTV and use of chemotherapy with anthracyclines and taxanes were associated with a greater acute toxicity. With a median follow-up of 31 months, no patients showed local or nodal relapse., Conclusions: A simplified step and shoot IMRT technique allowed better PTV coverage and reduced overall treatment time (CG, 6.6weeks; MARA-1, 3.2weeks; MARA-2, 5weeks) with acceptable short-term toxicity.

Background and Purpose: Quality assurance procedures (QA) may reduce the risk of errors in radiotherapy. The aim of this study was to assess a QA program based on independent check (IC) procedures in patients undergoing 3D, intensity modulated (IMRT) and extracranial stereotactic (ESRT) radiotherapy., Materials and Methods: IC for set-up (IC1) and for radiotherapy treatments (IC2) was tested on 622 patients over a year. Fifteen events/parameters and 17 parameters were verified by IC1 and IC2, respectively. A third evaluation check (IC3) was performed before treatment. Potential errors were classified based on their magnitude. Incidents involving only incorrect or incomplete documentation were segregated. Treatments were classified based on a complexity index (COMIX)., Results: With IC1, 75 documentation incidents and 31 potential errors were checked, and with IC2 111 documentation incidents and 6 potential errors were checked. During the study period 10 errors undetected by standard procedures (IC1, IC2) were detected by chance or by IC3. The incidence of errors and serious errors undetected by standard procedures was 1.6% and 0.6%, respectively. There was no higher incidence of errors undetected in patients undergoing IMRT or ESRT, while there was a higher incidence of errors undetected in more complex treatments (p < 0.001)., Conclusions: Systematic QA procedures can reduce the risk of errors. The risk of errors undetected by standard procedures is not correlated with the treatment technological level (3D versus IMRT/ESRT).

The case is reported of a patient with locally recurrent carcinoma of the tongue treated with intensity-modulated radiotherapy (IMRT) (simultaneous integrated boost) plus concurrent chemotherapy, who during the third week of radiotherapy developed grade 3 mucositis. Treatment was interrupted for 10 days until significant resolution of the symptoms. At the time of treatment resumption the patient showed 8% weight loss, and in vivo portal dose verification revealed large discrepancies between the computed and measured doses. A new CT scan showed marked tumor shrinkage and modifications to the critical structures. The comparison between the original plan and the hybrid IMRT showed a minimal dose increase in the new target volumes and a marked dose increase in the organs at risk. This case confirms the need for a robust quality assurance program when using IMRT, the feasibility and efficacy of in vivo dosimetry to detect significant discrepancies between planned and delivered dose, and the need to combine IMRT with 4-dimensional radiotherapy, at least for head and neck cancer.

As all methods for in-vivo dosimetry require special efforts many physicists are often discouraged in verifying the middle dose in a patient along the beam central axis. This work reports a practical method for the determination of the middle dose value, D(m), on the central beam axis, using a signal S(t), obtained by a small thimble ion-chamber positioned at the center of the electronic portal imaging device, and irradiated by the X-ray beam transmitted through the patient. The use of a stable ion-chamber reduces many of the disadvantages associated to the use of diodes as their periodic recalibration and time consuming positioning. The method makes use of a set of correlation functions obtained by the S(t) and D(m) ratios, determined by irradiating a water-equivalent phantom with 6 MV, 10 MV and 5 MV X-ray beams. Several tests were carried out in phantoms with asymmetric inhomogeneities. The method here proposed is based on the determination of the water-equivalent thickness of the patient, along the beam central axis, by the treatment planning system that makes use of the electron densities obtained by a computer tomography scanner, that works with calibrated Hounsfield numbers. This way, it is therefore possible to compare the dose, D(m, TPS), obtained by a treatment planning system, with the in-vivo dose D(m) value, both defined at density middle point (identified along the beam central axis, where the thick material, in terms of g cm(-2), above and below, is the same). The method has been applied for the in-vivo dosimetry of 30 patients, treated with conformed beams for pelvic tumor, checking: anterior-posterior or posterior-anterior irradiations and lateral-lateral irradiations. For every checked field at least five measurements were carried out. Applying a correct quality assurance program based on the tests of the patient set-up, machine settings and calculations, results showed that the method is able to verify agreements between the dose D(m,TPS) and the in-vivo dose value D(m), within 4% for 95% of the 240 measurements carried out in-vivo.

Total Skin Electron Therapy (TSET) was carried out using an electron beam with a nominal energy of 6 MeV. The beam was adequately filtered and angled in order to create dual fields. The uniformity of the dose distribution to the patient was 10%. The relative dosimetry of the dual beam was performed using a silicon diode and an ionization chamber in a standard water phantom. X-Omat V films were irradiated in a cylindrical PMMA phantom in order to obtain the dose distribution for the six TSET dual fields used in the treatment. Absolute dosimetry was carried out with a calibrated ionization chamber placed in a cylindrical water phantom. The dose contribution per monitor unit of the single dual beams was determined with this method.

The new radiotherapy techniques as HDR and LDR brachytherapy, stereotactic radiotherapy, 3D-CRT, and IMRT require an accurate knowledge of the biological characteristics of the tumor with correct definition of target volumes. As demonstrated by the two reported cases, the formulae equivalent to 2 Gy in the special techniques are useful for the increase in the total dose to GTV while sparing the organs at risk.

In the last two decades there was a radical change in radiotherapy setup. The growing availability of CT equipment and console for computer-aided treatment planning setup enabled the use of advanced technologies as conformal 3D radiation therapy in most centers. In particular in 1987 virtual simulation was proposed for setup. During its use a number of application modalities appeared. Virtual simulation in some centers is applied alone while in others it is associated with conventional simulation. However, from numerous reports published in last years it seems that virtual simulation significantly improves treatment quality independently of radical or palliative intent and of the size of treated volumes (high doses to small volumes or wide shaped fields). Some studies stressed that virtual simulation could significantly shorten treatment planning times with consequent cost reduction. The use of virtual simulation evidenced associated problems and in particular setup limitations due to the CT gantry size, the need to up-date the conventional modalities of setup verification according to the new technologies and more generally to up-date quality assurance procedures in an advanced technological setting. Finally there was the self-evident need of a better knowledge of the anatomy on axial sections, of tumor spread routes in particular.