Mario Ciocca

Full-Dose Intraoperative Radiotherapy With Electrons During Breast-Conserving Surgery: Experience With 590 Cases

Background:Previous studies show that local recurrences after breast-conserving treatment occur in the site of the primary tumor. The need for postoperative radiotherapy on the whole breast is challenged in favor of radiotherapy limited to the area of the breast at high risk of recurrence. The new mobile linear accelerators easily moved close to the operating table to allow the full-dose irradiation during surgery. Patients and Methods:From July 1999 to December 2003, 590 patients affected by unifocal breast carcinoma up to a diameter of 2.5 cm received wide resection of the breast followed by intraoperative radiotherapy with electrons (ELIOT). Most patients received 21 Gy intraoperatively, biologically equivalent to 58 to 60 Gy in standard fractionation. Patients were evaluated 1, 3, 6, and 12 months after surgery, and thereafter every 6 months, to look for early, intermediate, late complications, and other events. Results:After a follow-up from 4 to 57 months (mean, 24 months; median, 20 months), 19 patients (3.2%) developed breast fibrosis, mild in 18, severe in 1, which resolved within 24 months. Three patients (0.5%) developed local recurrences, 3 patients ipsilateral carcinomas in other quadrants and other 5 patients contralateral breast carcinoma. One patient (0.2%) died of distant metastases. Conclusions:ELIOT is a safe method for treating conservatively operated breasts, avoids the long period of postoperative radiotherapy, and reduces drastically the cost of radiotherapy. ELIOT reduces radiation to normal tissues and organs. Results on short-term and middle-term toxicity up to 5 years of follow-up are good. Data on local control are encouraging.

Intraoperative radiation therapy with electrons (ELIOT) in early-stage breast cancer.

Local recurrences after breast-conserving surgery occur mostly in the quadrant harbouring primary carcinoma. The main objective of postoperative radiotherapy should be the sterilisation of residual cancer cells in the operative area while irradiation of the whole breast may be avoided. We have developed a new technique of intraoperative radiotherapy of a breast quadrant after the removal of the primary carcinoma (ELIOT). A mobile linear accelerator with a robotic arm is utilised delivering electron beams able to produce energies from 3 to 9 MeV. Different dose levels were tested from 10 to 21 Gy without important side effects. A randomized trial is currently ongoing in order to compare conventional irradiation and ELIOT. More than 400 patients have been enrolled. In addition a new approach for nipple and areola complex conservation, including ELIOT, is under investigation.

PRELIMINARY RESULTS OF ELECTRON INTRAOPERATIVE THERAPY BOOST AND HYPOFRACTIONATED EXTERNAL BEAM RADIOTHERAPY AFTER BREAST-CONSERVING SURGERY IN PREMENOPAUSAL WOMEN

PURPOSE To report the acute and preliminary data on late toxicity of a pilot study of boost with electron intraoperative therapy followed by hypofractionated external beam radiotherapy (HEBRT) of the whole breast. METHODS AND MATERIALS Between June 2004 and March 2007, 211 women with a diagnosis of early-stage breast cancer were treated with breast-conserving surgery. During surgery, an electron intraoperative therapy boost of 12 Gy was administered to the tumor bed. Adjuvant local treatment was completed with HEBRT, consisting of a course of 13 daily fractions of 2.85 Gy to the whole breast to a total dose of 37.05 Gy. Acute toxicity of the breast was evaluated at the end of HEBRT and at 1 month of follow-up. Late toxicity was recorded at 6 and 12 months of follow-up. RESULTS We report the data from 204 patients. The maximal acute skin toxicity was observed at the end of HEBRT (182 patients evaluable) with 7 (3.8%) Grade 3, 52 (28.6%) Grade 2, 123 (67.6%) Grade 1, and no Grade 0 or Grade 4 cases. A total of 108 patients were evaluated for late toxicity. The recorded late skin toxicity was Grade 4 in 1 patient (0.9%), Grade 3 in 1 patient, and Grade 2 or less in 106 patients (98.2%). CONCLUSIONS The results of this study have shown that electron intraoperative therapy followed by HEBRT allows for the delivery of a high dose to the tumor bed and an adequate dose to the whole breast. This treatment is feasible, compliance is high, and the rate of acute toxicity and the preliminary data on chronic toxicity seem acceptable.

APPLICATION OF FAILURE MODE AND EFFECTS ANALYSIS TO INTRAOPERATIVE RADIATION THERAPY USING MOBILE ELECTRON LINEAR ACCELERATORS

PURPOSE Failure mode and effects analysis (FMEA) represents a prospective approach for risk assessment. A multidisciplinary working group of the Italian Association for Medical Physics applied FMEA to electron beam intraoperative radiation therapy (IORT) delivered using mobile linear accelerators, aiming at preventing accidental exposures to the patient. METHODS AND MATERIALS FMEA was applied to the IORT process, for the stages of the treatment delivery and verification, and consisted of three steps: 1) identification of the involved subprocesses; 2) identification and ranking of the potential failure modes, together with their causes and effects, using the risk probability number (RPN) scoring system, based on the product of three parameters (severity, frequency of occurrence and detectability, each ranging from 1 to 10); 3) identification of additional safety measures to be proposed for process quality and safety improvement. RPN upper threshold for little concern of risk was set at 125. RESULTS Twenty-four subprocesses were identified. Ten potential failure modes were found and scored, in terms of RPN, in the range of 42-216. The most critical failure modes consisted of internal shield misalignment, wrong Monitor Unit calculation and incorrect data entry at treatment console. Potential causes of failure included shield displacement, human errors, such as underestimation of CTV extension, mainly because of lack of adequate training and time pressures, failure in the communication between operators, and machine malfunctioning. The main effects of failure were represented by CTV underdose, wrong dose distribution and/or delivery, unintended normal tissue irradiation. As additional safety measures, the utilization of a dedicated staff for IORT, double-checking of MU calculation and data entry and finally implementation of in vivo dosimetry were suggested. CONCLUSIONS FMEA appeared as a useful tool for prospective evaluation of patient safety in radiotherapy. The application of this method to IORT lead to identify three safety measures for risk mitigation.

Transabdominal Ultrasonography, Computed Tomography and Electronic Portal Imaging for 3-Dimensional Conformal Radiotherapy for Prostate Cancer

Purpose:To evaluate the feasibility and accuracy of daily B-mode acquisition and targeting ultrasound-based prostate localization (BAT™) and to compare it with computed tomography (CT) and electronic portal imaging (EPI) in 3-dimensional conformal radiotherapy (3-D CRT) for prostate cancer.Patients and Methods:Ten patients were treated with 3-D CRT (72 Gy/30 fractions, 2.4 Gy/fraction, equivalent to 80 Gy/40 fractions, for α/β ratio of 1.5 Gy) and daily BAT-based prostate localization. For the first 5 fractions, CT and EPI were also performed in order to compare organ-motion and set-up error, respectively.Results:287 BAT-, 50 CT- and 46 EPI-alignments were performed. The average BAT-determined misalignments in latero-lateral, antero-posterior and cranio-caudal directions were –0.9 mm ± 3.3 mm, 1.0 mm ± 4.0 mm and –0.9 mm ± 3.8 mm, respectively. The differences between BAT- and CT-determined organ-motion in latero-lateral, antero-posterior and cranio-caudal directions were 2.7 mm ± 1.9 mm, 3.9 ± 2.8 mm and 3.4 ± 3.0 mm, respectively. Weak correlation was found between BAT- and CT-determined misalignments in antero-posterior direction, while no correlation was observed in latero-lateral and cranio-caudal directions. The correlation was more significant when only data of good image-quality patients were analyzed (8 patients).Conclusion:BAT ensures the relative positions of target are the same during treatment and in treatment plan, however, the reliability of alignment is patient-dependent. The average BAT-determined misalignments were small, confirming the prevalence of random errors in 3-D CRT. Further study is warranted in order to establish the clinical value of BAT.Ziel:Ziel dieser Studie ist es, die Möglichkeit und Genauigkeit der täglichen B-mode-Akquisition und zielgerichteten ultraschallbasierten Prostatapositionierung (BAT™) einzuschätzen und sie mit der Computertomographie (CT) und dem elektronischen Portal-Imaging (EPI) bei der 3D-konformalen Strahlentherapie (3D-CRT) des Prostatakrebses zu vergleichen.Patienten und Methodik:10 Patienten wurden mit 3D-CRT (72 Gy/30 Fraktionen, 2,4 Gy/Fraktion, äquivalent zu 80 Gy/40 Fraktionen, α/β-Verhältnis von 1,5 Gy ) und täglicher BAT behandelt. Für die ersten 5 Fraktionen wurden auch CT und EPI durchgeführt, um jeweils die Bewegung der Organe und die Set-up-Fehler zu vergleichen.Ergebnisse:287 BAT-, 50 CT- und 46 EPI-Positionierungen wurden durchgeführt. Der durchschnittliche BAT-Positionierungsfehler war jeweils –0,9 mm ± 3,3 mm, 1,0 mm ± 4,0 mm und –0,9 mm ± 3,8 mm in den latero-lateralen, anterior-posterioren und kraniokaudalen Richtungen. Die Unterschiede zwischen der BAT- und CT-Technik bei der Bestimmung der Organbewegung in den latero-lateralen, anterior-posterioren und kraniokaudalen Richtungen waren jeweils 2,7 mm ± 1,9 mm, 3,9 ± 2,8 mm und 3,4 ± 3,0 mm. Eine sehr geringe Korrelation zwischen BAT- und CT-Positionierungsungenauigkeit wurde nur für die anterior-posteriore Richtung gefunden (R = 0,29, p = 0,04). Die Korrelation war leicht besser, wenn nur die Patienten mit guter Bildqualität analysiert wurden (8 Patienten).Schlussfolgerung:BAT garantiert, dass die relative Position des Ziels dieselbe während der Behandlung und in dem Behandlungsplan ist, obwohl die Genauigkeit der Positionierung patientenabhängig ist. Die durchschnittlichen, mit BAT bestimmten, Positionierungsfehler waren klein und bestätigen, dass der statistische Fehler in 3D-CRT vorwiegend ist. Weitere Studien sind erforderlich, um den klinischen Wert von BAT festzustellen.

Application of failure mode and effects analysis to treatment planning in scanned proton beam radiotherapy

BackgroundA multidisciplinary and multi-institutional working group applied the Failure Mode and Effects Analysis (FMEA) approach to the actively scanned proton beam radiotherapy process implemented at CNAO (Centro Nazionale di Adroterapia Oncologica), aiming at preventing accidental exposures to the patient.MethodsFMEA was applied to the treatment planning stage and consisted of three steps: i) identification of the involved sub-processes; ii) identification and ranking of the potential failure modes, together with their causes and effects, using the risk probability number (RPN) scoring system, iii) identification of additional safety measures to be proposed for process quality and safety improvement. RPN upper threshold for little concern of risk was set at 125.ResultsThirty-four sub-processes were identified, twenty-two of them were judged to be potentially prone to one or more failure modes. A total of forty-four failure modes were recognized, 52% of them characterized by an RPN score equal to 80 or higher. The threshold of 125 for RPN was exceeded in five cases only. The most critical sub-process appeared related to the delineation and correction of artefacts in planning CT data. Failures associated to that sub-process were inaccurate delineation of the artefacts and incorrect proton stopping power assignment to body regions. Other significant failure modes consisted of an outdated representation of the patient anatomy, an improper selection of beam direction and of the physical beam model or dose calculation grid. The main effects of these failures were represented by wrong dose distribution (i.e. deviating from the planned one) delivered to the patient. Additional strategies for risk mitigation, easily and immediately applicable, consisted of a systematic information collection about any known implanted prosthesis directly from each patient and enforcing a short interval time between CT scan and treatment start. Moreover, (i) the investigation of dedicated CT image reconstruction algorithms, (ii) further evaluation of treatment plan robustness and (iii) implementation of independent methods for dose calculation (such as Monte Carlo simulations) may represent novel solutions to increase patient safety.ConclusionsFMEA is a useful tool for prospective evaluation of patient safety in proton beam radiotherapy. The application of this method to the treatment planning stage lead to identify strategies for risk mitigation in addition to the safety measures already adopted in clinical practice.

Neutron production from a mobile linear accelerator operating in electron mode for intraoperative radiation therapy

Intraoperative electron beam radiotherapy is increasingly performed using mobile linac delivering therapeutic radiation doses in unshielded operating rooms. While no special neutron-shielding problem should arise for operation at 10 MeV or less, it is not clear whether this holds true for operation at higher energies. This paper reports the measured neutron production from a Mobetron mobile electron linac, operated at 12 MeV, and compares the results with those from a conventional linac, also operated at 12 MeV in electron mode. Neutron leakage measurements were performed by means of passive bubble detectors in the scattering foil, patient and floor planes. Neutron dose equivalent rates per unit of electron dose delivered by the Mobetron at its normal treatment distance (50 cm SSD) were 0.33 microSv Gy(-1) at the accelerator head, 0.18 microSv Gy(-1) in the patient plane at 15 cm from the beam axis and 0.31 microSv Gy(-1) at the floor plane, on the beam axis and under the beam stopper. For a weekly workload of 250 Gy, the weekly neutron dose equivalents at 12 MeV for the Mobetron at a distance of 300 cm from the scattering foil were 14.3 and 1.7 microSv/week for floor below and adjoining areas on the same floor, respectively. Neutron dose equivalent rates generated from Mobetron are at least one order of magnitude lower than ones produced by a conventional linac operated at the same energy in electron mode. Mobetron can be used at 12 MeV in an unshielded operating room for a weekly workload of up to 250 Gy if the bremsstrahlung x-rays are shielded to negligible levels.

Dosimetric commissioning and quality assurance of scanned ion beams at the Italian National Center for Oncological Hadrontherapy.

PURPOSE To describe the dosimetric commissioning and quality assurance (QA) of the actively scanned proton and carbon ion beams at the Italian National Center for Oncological Hadrontherapy. METHODS The laterally integrated depth-dose-distributions (IDDs) were acquired with the PTW Peakfinder, a variable depth water column, equipped with two Bragg peak ionization chambers. fluka Monte Carlo code was used to generate the energy libraries, the IDDs in water, and the fragment spectra for carbon beams. EBT3 films were used for spot size measurements, beam position over the scan field, and homogeneity in 2D-fields. Beam monitor calibration was performed in terms of number of particles per monitor unit using both a Farmer-type and an Advanced Markus ionization chamber. The beam position at the isocenter, beam monitor calibration curve, dose constancy in the center of the spread-out-Bragg-peak, dose homogeneity in 2D-fields, beam energy, spot size, and spot position over the scan field are all checked on a daily basis for both protons and carbon ions and on all beam lines. RESULTS The simulated IDDs showed an excellent agreement with the measured experimental curves. The measured full width at half maximum (FWHM) of the pencil beam in air at the isocenter was energy-dependent for both particle species: in particular, for protons, the spot size ranged from 0.7 to 2.2 cm. For carbon ions, two sets of spot size are available: FWHM ranged from 0.4 to 0.8 cm (for the smaller spot size) and from 0.8 to 1.1 cm (for the larger one). The spot position was accurate to within ± 1 mm over the whole 20 × 20 cm(2) scan field; homogeneity in a uniform squared field was within ± 5% for both particle types at any energy. QA results exceeding tolerance levels were rarely found. In the reporting period, the machine downtime was around 6%, of which 4.5% was due to planned maintenance shutdowns. CONCLUSIONS After successful dosimetric beam commissioning, quality assurance measurements performed during a 24-month period show very stable beam characteristics, which are therefore suitable for performing safe and accurate patient treatments.

Intra‐tumoral Salmonella typhimurium induces a systemic anti‐tumor immune response that is directed by low‐dose radiation to treat distal disease

Salmonella typhimurium is a facultative anaerobic bacterium able to multiply preferentially in tumors and inhibit their growth. The mechanisms through which Salmonella exerts its anti‐cancer properties are not fully understood. We recently showed that intra‐tumoral Salmonella injection results not only in the regression of even bulky tumor masses, but also impacts on the growth of distant untreated lesions. Here we describe how Salmonella exerts its systemic anti‐cancer effects and means to potentiate them. The outburst of an early inflammatory reaction in the treated tumor promotes the development of an immunostimulatory cytokine environment both locally and in the draining lymph node. Within the next 10 days, an efficient cross‐presentation of endogenous tumor antigens by dendritic cells at the tumor‐draining lymph node leads to the priming of effective anti‐tumor CD8+ T cell responses. This potentially broadly reactive T cell repertoire can be directed to other pre‐established melanomas by low‐dose radiotherapy enhancing the Salmonella anti‐cancer effect. We demonstrate that Salmonella‐based therapy coupled to low‐dose radiotherapy dampens tumor immune escape mechanisms at different levels and allows controlling systemic disease in a CD8+ T cell‐dependent manner.

A new option for early breast cancer patients previously irradiated for Hodgkin's disease: intraoperative radiotherapy with electrons (ELIOT)

IntroductionPatients who have undergone mantle radiotherapy for Hodgkins disease (HD) are at increased risk of developing breast cancer. In such patients, breast conserving surgery (BCS) followed by breast irradiation is generally considered contraindicated owing to the high cumulative radiation dose. Mastectomy is therefore recommended as the first option treatment in these women.MethodsSix patients affected by early breast cancer previously treated with mantle radiation for HD underwent BCS associated with full-dose intraoperative radiotherapy with electrons (ELIOT).ResultsA total dose of 21 Gy (prescribed at 90% isodose) in five cases and 17 Gy (at 100% isodose) in one case were delivered directly to the mammary gland without acute complications and with good cosmetic results. After an average of 30.8 months of follow up, no late sequelae were observed and the patients are free of disease.ConclusionIn patients previously irradiated for HD, ELIOT can avoid repeat irradiation of the whole breast, permit BCS and decrease the number of avoidable mastectomies.