L. Marrazzo

Accelerated partial breast irradiation using intensity-modulated radiotherapy versus whole breast irradiation: 5-year survival analysis of a phase 3 randomised controlled trial

BACKGROUND Accelerated partial breast irradiation (APBI) has been introduced as an alternative treatment method for selected patients with early stage breast cancer (BC). Intensity-modulated radiotherapy (IMRT) has the theoretical advantage of a further increase in dose conformity compared with three-dimensional techniques, with more normal tissue sparing. The aim of this randomised trial is to compare the local recurrence and survival of APBI using the IMRT technique after breast-conserving surgery to conventional whole-breast irradiation (WBI) in early stage BC. METHODS This study was performed at the University of Florence (Florence, Italy). Women aged more than 40years affected by early BC, with a maximum pathological tumour size of 25mm, were randomly assigned in a 1:1 ratio to receive either WBI or APBI using IMRT. Patients in the APBI arm received a total dose of 30 Gy to the tumour bed in five daily fractions. The WBI arm received 50Gy in 25 fractions, followed by a boost on the tumour bed of 10Gy in five fractions. The primary end-point was occurrence of ipsilateral breast tumour recurrences (IBTRs); the main analysis was by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT02104895. FINDINGS A total of 520 patients were randomised (260 to external WBI and 260 to APBI with IMRT) between March 2005 and June 2013. At a median follow-up of 5.0 years (Interquartile Range (IQR) 3.4-7.0), the IBTR rate was 1.5% (three cases) in the APBI group (95% confidence interval (CI) 0.1-3.0) and in the WBI group (three cases; 95% CI 0.0-2.8). No significant difference emerged between the two groups (log rank test p=0.86). We identified seven deaths in the WBI group and only one in the APBI group (p=0.057). The 5-year overall survival was 96.6% for the WBI group and 99.4% for the APBI group. The APBI group presented significantly better results considering acute (p=0.0001), late (p=0.004), and cosmetic outcome (p=0.045). INTERPRETATION To our knowledge, this is the first randomised study using the IMRT technique for APBI delivery. No significant difference in terms of IBTR and overall survival was observed between the two arms. APBI displayed a significantly better toxicity profile.

Accelerated Partial Breast Irradiation With IMRT: New Technical Approach and Interim Analysis of Acute Toxicity in a Phase III Randomized Clinical Trial

PURPOSE To evaluate with a randomized clinical trial the possibility of treating the index quadrant with external intensity-modulated radiotherapy (IMRT) in a selected group of patients with early-stage breast cancer and to analyze the acute toxicity. METHODS AND MATERIALS From September 2005, a randomized Phase III clinical trial has been conducted to compare conventional (tangential field) fractionated whole breast treatment (Arm A) with accelerated partial breast irradiation plus intensity-modulated radiotherapy (Arm B). For intensity-modulated radiotherapy, the clinical target volume was drawn with a uniform 1-cm margin around the surgical clips in three dimensions. The ipsilateral and contralateral breast, ipsilateral and contralateral lung, heart, and spinal cord were contoured as organs at risk. All the regions of interest were contoured according to the International Commission on Radiation Units and Measurements reports 50 and 62 recommendations. RESULTS In September 2008, 259 patients were randomized and treated. The mean clinical target volume in Arm B was 44 cm(3) and the mean planning target volume was 123 cm(3). The mean value of the ratio between the planning target volume and the ipsilateral breast volume was 21%. The rate of Grade 1 and Grade 2 acute skin toxicity was 22% and 19% in Arm A (Radiation Therapy Oncology Group scale), respectively. The tolerance in Arm B was excellent with only 5% Grade 1 and 0.8% Grade 2 acute skin toxicity. The planning constraints were fully satisfied in most patients. In a very few cases, this was not possible because of very unfavorable anatomy. Quality assurance procedures were performed according to our internal quality assurance protocol, with excellent results. CONCLUSION In the present preliminary analysis, we have demonstrated that accelerated partial breast irradiation is feasible, with very low acute toxicity.

Adjuvant radiotherapy after extrapleural pneumonectomy for mesothelioma. Prospective analysis of a multi-institutional series

BACKGROUND AND PURPOSE To evaluate survival, locoregional control and toxicity in a series of 56 mesothelioma patients treated from May 2005 to May 2010 with post-operative radiotherapy after extrapleural pneumonectomy (EPP) in three Italian Institutions (Brescia, Florence, and Modena). MATERIAL AND METHODS Fifty-six patients treated with adjuvant radiotherapy (RT) after EPP were analyzed. Four patients were treated with 3DCRT, 50 with IMRT and two with helical tomotherapy. Forty-five to 50 Gy in 25 fractions were given to the affected hemithorax and to ipsilateral mediastinum, with a simultaneous integrated boost to the sites of microscopically involved margins up to 60 Gy in 20/56 cases. RESULTS Three year locoregional control (LRC), distant metastasis free (DMF), disease free (DF), disease specific (DSS) and overall survival (OS) rates are 90%, 66%, 57%, 62%, and 60%, respectively. CONCLUSION Postoperative RT with modern techniques is an effective method to obtain excellent local control and cure rates in mesothelioma patients submitted to EPP.

Characterization of a Silicon Strip Detector and a YAG:Ce Calorimeter for a Proton Computed Radiography Apparatus

Today, there is a steadily growing interest in the use of proton beams for tumor therapy, as they permit to tightly shape the dose delivered to the target reducing the exposure of the surrounding healthy tissues. Nonetheless, accuracy in the determination of the dose distribution in proton-therapy is up to now limited by the uncertainty in stopping powers, which are presently calculated from the photon attenuation coefficients measured by X-ray tomography. Proton computed tomography apparatus (pCT) has been proposed to directly measure the stopping power and reduce this uncertainty. Main problem with proton imaging is the blurring effect introduced by multiple Coulomb scattering: single proton tracking is a promising technique to face this difficulty. As a first step towards a pCT system, we designed a proton radiography (pCR) prototype based on a silicon microstrip tracker (to characterize particle trajectories) and a segmented YAG:Ce calorimeter (to measure their residual energy). Aim of the system is to detect protons with a ~1 MHz particle rate of and with kinetic energy in the range 250-270 MeV, high enough to pass through human body. Design and development of the pCR prototype, as well as the characterization of its single components, are described in this paper.

Post-operative radiotherapy in N2 non-small cell lung cancer: A retrospective analysis of 175 patients

BACKGROUND AND PURPOSE Post-operative radiotherapy (PORT) in radically resected non-small cell lung cancer (NSCLC) has the aim to reduce loco regional recurrence and to improve overall survival. PORT has been evaluated in several trials but indication to post-operative treatment in N2 patients is still debated. MATERIAL AND METHODS We retrospectively analyzed 175 patients treated at University of Florence between 1988 and 2004 with completely resected NSCLC stages IIIA-IIIB, N2 disease. Surgery consisted in a lobectomy in 58.9% and in a bi-lobectomy or in a pneumonectomy in 41.1% of patients. One hundred and nineteen patients underwent PORT and 56 patients did not receive PORT (no-PORT). RESULTS At a median follow-up of 27.6 months (range 4-233 months), we found a significant reduction in local recurrence (LR) in PORT group (log-rank test p=0.015; HR: 0.45; 95%CI: 0.24-0.87). No statistical difference were found in terms of overall survival (OS) (log-rank test p=0.92). Concerning other prognostic factors, male sex emerged as statistically significant (HR:4.33;1.04-18.02) on local progression free survival (LPFS) at univariate analysis. Acute and long-term toxicity was mild. CONCLUSION Our retrospective analysis showed that PORT may improve local disease control in N2 NSCLC patients with an acceptable treatment-related toxicity.

OUTCOME AFTER CONSERVATIVE SURGERY AND BREAST IRRADIATION IN 5,717 PATIENTS WITH BREAST CANCER: IMPLICATIONS FOR SUPRACLAVICULAR NODAL IRRADIATION

PURPOSE To evaluate the outcome and predictive factors of patients who underwent breast-conserving surgery and adjuvant radiotherapy to the whole breast only, without supraclavicular nodal irradiation. METHODS AND MATERIALS A total of 5,717 patients with pT1-T4 breast cancer were treated at the University of Florence. The median age of the patient population was 55 years (range, 30-80 years). All patients were followed for a median of 6.8 years (range, 1-27 years). Adjuvant chemotherapy was recommended in 1,535 patients (26.9%). Tamoxifen was prescribed in 2,951 patients (51.6%). The patients were split into three groups according to number of positive axillary nodes (PAN): P1, negative axillary lymph nodes; P2, one to three PAN; P3, more than three PAN. RESULTS The P3 patients had a higher incidence of supraclavicular fossa recurrence (SFR) compared with P2 and P1 patients. However, the incidence of SFR in P3 patients was low (only 5.5%), whereas the incidence of distant metastases (DM) was 27.2%. Distant metastasis was the only independent prognostic factor for breast cancer survival. Additionally, in the subgroup of patients who developed local recurrence, DM was the most important death predictor. CONCLUSION Our series suggests that isolated SFR in patients who did not receive supraclavicular radiotherapy is infrequent, as well as in those patients who have more than three PAN, and SFR seems not to influence the outcome, which depends on DM occurrence.

A phantom evaluation of Sentinel™, a commercial laser/camera surface imaging system for patient setup verification in radiotherapy

PURPOSE The aim of this study is to investigate the performance of Sentinel(™), a patient setup verification device based on a laser/camera system, when used on rigid-body phantoms. METHODS The Sentinel system consists of a scanner unit, containing the laser and the camera, and surface-matching registration software. For the registration procedure, both a computed tomography (CT) and a Sentinel image can be used as a reference. Tests were performed on phantoms using an Elekta Synergy(®) beam modulator Linac equipped with a cone beam CT (CBCT), a HexaPOD RT couch top, and an iViewGT portal imaging system. Experiments conducted in this study tested reproducibility of the Sentinel surface acquisition and of set-up procedure, accuracy in quantifying known phantom mispositioning, and compared Sentinel, CBCT, and portal imaging system performance. RESULTS Reproducibility of surface acquisition and setup procedure was better than 0.5 mm and 0.5° and 1 mm and 0.4°, respectively. The system accuracy was better than 1 mm and 1° when a Sentinel image was used as reference. A global worsening of Sentinel performance was observed using as reference an external surface extracted from CT study. This effect is probably due to small differences in considered surfaces, caused by different imaging modalities. The results obtained by testing the system on rigid phantoms were comparable to those obtained using CBCT and better than those obtained with conventional portal imaging systems. CONCLUSIONS The Sentinel setup verification device is a reproducible and consistent system able to detect misalignments with accuracy better than 1 mm and 1°. When tested on rigid body phantoms, Sentinel and CBCT performed similarly. When compared to portal imaging, both Sentinel and CBCT were more accurate.

Design and implementation of a water phantom for IMRT, arc therapy, and tomotherapy dose distribution measurements.

The aim of this paper is to present a new phantom for arc therapy, intensity-modulated radiation therapy (IMRT), and tomotherapy dose distribution measurement in pretreatment verification. The presented phantom is innovative for its use of water as the tissue equivalent material, together with a technical solution specifically designed to support radiographic or radiochromic film and ionization chambers in any desired position. The phantom comprise a Plexiglas container, whose present shape and dimensions offer the possibility to simulate a human torso or abdomen; the container can be filled with water by opening the upper cover. On the internal side of the cover, a set of carbon pipes can support film in the desired coronal, axial, or sagittal planes. At one of the two ends of the phantom, an ionization chamber can be positioned parallel to the rotation axis of the accelerator gantry in all possible positions within a 20 cm diameter cylinder, for film calibration purposes. Inhomogeneities can be inserted into the phantom using the same carbon pipes and plastic sheets used to support film. An example of vertebra-shaped inserts made of bone equivalent material is reported. Radiochromic film can be dipped in water, while radiographic film must be protected to prevent damage. To accomplish this, radiographic film is laminated using a cold laminating film. In order to assess the effects of both the lamination itself and the effects of water on laminated Kodak EDR2 film, the optical density (OD) of conventional, laminated, and laminated film immersed in water and exposed to a range of doses from 0 to 300 cGy were compared. The OD of the three samples receiving the same radiation dose did not present any significant difference, thus proving that laminated EDR2 film can also be used in water. A prerequisite for any dosimetric comparison between planned and measured data is a proper film to plan registration. The solution proposed here is an extrinsic in-plane registration technique using four reference points marked on each film in predefined positions. The four points and the millimeter scales fixed on the carbon pipes that support the film are designed and manufactured so as to transfer onto the film the same reference system used during the planning procedure, thus allowing a straightforward registration. Tests to assess the accuracy of the proposed registration method demonstrate that the distances between measured and intended marker positions, evaluated for coronal, axial, and sagittal planes, were about 1 mm for both anteroposterior and lateral projections.

Radiotherapy boost dose-escalation for invasive breast cancer after breast-conserving surgery: 2093 Patients treated with a prospective margin-directed policy

PURPOSE To investigate the outcome of invasive early breast cancer patients that underwent breast-conserving surgery and adjuvant radiotherapy (RT), treated with a prospective margin-directed institutional policy for RT boost dose, based on final margins status (FMS). METHODS AND MATERIALS A total of 2093 patients were treated between 2000 and 2008. 10 Gy boost was prescribed in case of FMS>5mm; 16 Gy boost with FMS between 2 and 5mm; 20 Gy boost in case of FMS<2mm or positive. RESULTS After a median follow up of 5.2 years, we recorded 41 local relapse (LR, 2%). Concerning LR free survival, age at diagnosis, nuclear grade, hormonal status, T-stage, adjuvant hormonal therapy and adjuvant chemotherapy emerged as significant parameters (p-values from log rank test <0.05). FMS, that directed the RT boost dose, did not have significant impact on LRFS (p=0.46). LR rates were 2.3% for FMS<2mm, 2.6% for 2-5mm FMS and 1.8% for FMS>5mm. At multivariate analysis, higher nuclear grade (p=0.045), triple negative subtype (p=0.036) and higher T-stage (p=0.02) resulted as the independent predictors of LR occurrence. CONCLUSIONS Our experience showed that a margin-directed policy of RT boost dose-escalation seems to reduce the negative impact of FMS on LR, but it is not able to overcome the unfavorable effect of higher nuclear grade, higher T stage and triple negative subtype.

Prognostic factors and clinical features in patients with leptominengeal metastases from breast cancer: a single center experience

Abstract Background: Meningeal carcinomatosis (MC) is a rare complication in breast cancer (BC) with no efficient modality of treatment yet found; overall survival (OS) generally did not exceed six months. We reviewed the experience of the University of Florence focusing on prognostic factors and MC survival. Patients and methods: We analyzed 33 patients treated for MC from BC between 2002 and 2010. Results: Mean OS from MC diagnosis was 4·9 months. At survival analysis clinical stage emerged as the only statistical significant parameter (P = 0·009) among BC diagnosis features. Among MC diagnosis parameters, more than three metastases at diagnosis (P = 0·037), multimodality treatment (P = 0·014) and poor performance status (P = 0·003) reached the statistical significance. At multivariate analysis only performance status at MC diagnosis maintained the statistical significance (P = 0·0047; HR: 3·34; CI 95% 1·45–7·73). Conclusions: Our experience confirms that performance status is probably the most important prognostic factor in these patients. Multimodality approach is probably the best option.