J. Krayenbuehl

Neoadjuvant chemotherapy and extrapleural pneumonectomy of malignant pleural mesothelioma with or without hemithoracic radiotherapy (SAKK 17/04): a randomised, international, multicentre phase 2 trial

BACKGROUND Postoperative hemithoracic radiotherapy has been used to treat malignant pleural mesothelioma, but it has not been assessed in a randomised trial. We assessed high-dose hemithoracic radiotherapy after neoadjuvant chemotherapy and extrapleural pneumonectomy in patients with malignant pleural mesothelioma. METHODS We did this phase 2 trial in two parts at 14 hospitals in Switzerland, Belgium, and Germany. We enrolled patients with pathologically confirmed malignant pleural mesothelioma; resectable TNM stages T1-3 N0-2, M0; WHO performance status 0-1; age 18-70 years. In part 1, patients were given three cycles of neoadjuvant chemotherapy (cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) on day 1 given every 3 weeks) and extrapleural pneumonectomy; the primary endpoint was complete macroscopic resection (R0-1). In part 2, participants with complete macroscopic resection were randomly assigned (1:1) to receive high-dose radiotherapy or not. The target volume for radiotherapy encompassed the entire hemithorax, the thoracotomy channel, and mediastinal nodal stations if affected by the disease or violated surgically. A boost was given to areas at high risk for locoregional relapse. The allocation was stratified by centre, histology (sarcomatoid vs epithelioid or mixed), mediastinal lymph node involvement (N0-1 vs N2), and T stage (T1-2 vs T3). The primary endpoint of part 1 was the proportion of patients achieving complete macroscopic resection (R0 and R1). The primary endpoint in part 2 was locoregional relapse-free survival, analysed by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00334594. FINDINGS We enrolled patients between Dec 7, 2005, and Oct 17, 2012. Overall, we analysed 151 patients receiving neoadjuvant chemotherapy, of whom 113 (75%) had extrapleural pneumonectomy. Median follow-up was 54·2 months (IQR 32-66). 52 (34%) of 151 patients achieved an objective response. The most common grade 3 or 4 toxic effects were neutropenia (21 [14%] of 151 patients), anaemia (11 [7%]), and nausea or vomiting (eight [5%]). 113 patients had extrapleural pneumonectomy, with complete macroscopic resection achieved in 96 (64%) of 151 patients. We enrolled 54 patients in part 2; 27 in each group. The main reasons for exclusion were patient refusal (n=20) and ineligibility (n=10). 25 of 27 patients completed radiotherapy. Median total radiotherapy dose was 55·9 Gy (IQR 46·8-56·0). Median locoregional relapse-free survival from surgery, was 7·6 months (95% CI 4·5-10·7) in the no radiotherapy group and 9·4 months (6·5-11·9) in the radiotherapy group. The most common grade 3 or higher toxic effects related to radiotherapy were nausea or vomiting (three [11%] of 27 patients), oesophagitis (two [7%]), and pneumonitis (two [7%]). One patient died of pneumonitis. We recorded no toxic effects data for the control group. INTERPRETATION Our findings do not support the routine use of hemithoracic radiotherapy for malignant pleural mesothelioma after neoadjuvant chemotherapy and extrapleural pneumonectomy. FUNDING Swiss Group for Clinical Cancer Research, Swiss State Secretariat for Education, Research and Innovation, Eli Lilly.

PROTON THERAPY FOR MALIGNANT PLEURAL MESOTHELIOMA AFTER EXTRAPLEURAL PLEUROPNEUMONECTOMY

PURPOSE To perform comparative planning for intensity-modulated radiotherapy (IMRT) and proton therapy (PT) for malignant pleural mesothelioma after radical surgery. METHODS AND MATERIALS Eight patients treated with IMRT after extrapleural pleuropneumonectomy (EPP) were replanned for PT, comparing dose homogeneity, target volume coverage, and mean and maximal dose to organs at risk. Feasibility of PT was evaluated regarding the dose distribution with respect to air cavities after EPP. RESULTS Dose coverage and dose homogeneity of the planning target volume (PTV) were significantly better for PT than for IMRT regarding the volume covered by >95% (V95) for the high-dose PTV. The mean dose to the contralateral kidney, ipsilateral kidney, contralateral lung, liver, and heart and spinal cord dose were significantly reduced with PT compared with IMRT. After EPP, air cavities were common (range, 0-850 cm(3)), decreasing from 0 to 18.5 cm(3)/day. In 2 patients, air cavity changes during RT decreased the generalized equivalent uniform dose (gEUD) in the case of using an a value of < - 10 to the PTV2 to <2 Gy in the presence of changing cavities for PT, and to 40 Gy for IMRT. Small changes were observed for gEUD of PTV1 because PTV1 was reached by the beams before air. CONCLUSION Both PT and IMRT achieved good target coverage and dose homogeneity. Proton therapy accomplished additional dose sparing of most organs at risk compared with IMRT. Proton therapy dose distributions were more susceptible to changing air cavities, emphasizing the need for adaptive RT and replanning.

Intensity-modulated radiotherapy and volumetric-modulated arc therapy for malignant pleural mesothelioma after extrapleural pleuropneumonectomy

Radiotherapy reduces the local relapse rate after pleuropneumonectomy of malignant pleural mesothelioma (MPM). The optimal treatment technique with photons remains undefined. Comparative planning for intensity‐modulated radiotherapy (IMRT) and volumetric‐modulated arc therapy (VMAT) was performed. Six MPM patients with significant postoperative intrathoracic air cavities were planned with IMRT and VMAT. A dose comparison for the targets and organ at risks (OAR) was performed. Robustness was assessed in respect to the variation of target dose with change in volume of air cavities. VMAT reduced the dose to the contralateral lung by reducing the volume covered by 13 Gy and 20 Gy by a factor 1.8 and 2.8, in respect to IMRT (p=0.02). Dose distribution with VMAT was the most stable technique in regard to postsurgical air cavity variation. For IMRT, V90,V95, and the minimal target dose decreased by 40%, 64%, and 12% compared to 29%, 47%, and 7% with VMAT when air cavity decreased. Two arcs compared to one arc decreased the dose to all the organs at risk (OAR) while leaving PTV dose coverage unchanged. Increasing the number of arcs from two to three did not reduce the dose to the OAR further, but increased the beam‐on time by 50%. Using partial arcs decreased the beam‐on time by 43%. VMAT allows a lower lung dose and is less affected by the air cavity variation than IMRT. The best VMAT plans were obtained with two partial arcs. VMAT seems currently the most suitable technique for the treatment of MPM patients when air cavities are remaining and no adaptive radiotherapy is performed. PACS number: 87.55.D‐

Clinical outcome of postoperative highly conformal versus 3D conformal radiotherapy in patients with malignant pleural mesothelioma

BackgroundRadiotherapy (RT) is currently under investigation as part of a trimodality treatment of malignant pleural mesothelioma (MPM). The introduction of highly conformal radiotherapy (HCRT) technique improved dose delivery and target coverage in comparison to 3-dimensional conformal radiotherapy (3DCRT). The following study was undertaken to investigate the clinical outcome of both radiation techniques.MethodsThirty-nine MPM patients were treated with neoadjuvant chemotherapy, extrapleural pneumonectomy (EPP) and adjuvant RT. Twenty-five patients were treated with 3DCRT, and 14 with HCRT (Intensity modulated radiotherapy or volumetric modulated arc therapy). Overall survival, disease free survival, locoregional recurrence and pattern of recurrence were assessed. A matched pair analysis was performed including 11 patients of each group.ResultsAfter matching for gender, age, histology, tumor stage and resection status, HCRT seemed superior to 3DCRT with a local relapse rate of 27.3% compared to 72.7% after 3DCRT (p = 0.06). The median time to local relapse was increased by 49% with HCRT in comparison to 3DCRT from 10.9 ± 5.4 months to 16.2 ± 3.1 months (p = 0.06). The median overall survival was 22.3 ± 15.3 months for HCRT and 21.2 ± 9.2 months for 3DCRT (p = 0.57). Recurrence analysis showed that in-field local relapses occurred in previously underdosed regions of the tumor bed in 16% of patients treated with 3DCRT and in 0% of HCRT patients.ConclusionsThe use of HCRT increases the probability of local control as compared to 3DCRT by improving target volume coverage. HCRT did not improve overall survival in this patient series due to the high rate of distant recurrences.

Implementation and validation of a new fixation system for stereotactic radiation therapy: An analysis of patient immobilization

PURPOSE Stereotactic radiation therapy is an established treatment technique for intracranial malignancies. We evaluated a new intracranial immobilization system with an emphasis on determining the intrafraction motion and the correlation of this motion with treatment time. METHODS AND MATERIALS Patients were immobilized using the trUpoint ARCH fixation system (CIVCO Medical Solutions). We collected data from 85 lesions in 73 patients treated between November 2011 and December 2013. Sixty-nine of 73 patients (95%) used the complete mask system; for the remaining 4 patients, the system had to be adapted. Patients were treated using volumetric modulated arc therapy stereotactic radiation therapy on a TrueBeam linear accelerator (Varian Medical Systems, Palo Alto, CA). Fraction doses of 2-8 Gy were applied in 4-30 fractions. Daily cone beam computed tomography imaging was performed before the treatment and was matched to the reference computed tomography using a 6-degrees-of-freedom automatching procedure. Additionally, posttreatment cone beam computed tomography scans were performed to assess intrafraction motion for 67 patients (375 fractions). RESULTS The average 3-dimensional setup error was 2.1 ± 2.9 mm. The mean pitch and roll was -0.1 ± 0.7° and 0.2 ± 0.7°. A total of 98.0% of the pitch values and 98.9% of the roll values were <1.5°. Mean intrafractional motion was 0.51 mm (±0.27) and mean treatment time was 10.1 minutes (±1.4). The maximum intrafractional motion was 2.0 mm in the longitudinal direction; 95% of the total shifts were <1.4 mm. The linear regression showed a weak but significant influence (R(2) = 0.26, P = .01) of the treatment time on the total intrafractional shift. CONCLUSIONS The new intracranial immobilization system appears to be robust in terms of setup accuracy, intrafraction motion, and repositioning of the mask system.

Optimizing radiosurgery with photons for ocular melanoma

Background and purpose Photon radiotherapy has been established for the treatment of ocular melanoma (OM). Here we investigate the planning qualities of two different planning approaches, a combination of dynamic conformal arcs (DCA) complemented with multiple non-coplanar static intensity-modulated (IMRT) fields (DCA-IMRT), and volumetric modulated arc therapy (VMAT) in combination with automated planning (AP). Materials and methods Thirteen consecutive patients treated for ocular melanoma with curative intent on a Linac-based radiosurgery system were analyzed. Fractionated stereotactic radiosurgery (fSRS) was applied using 50 Gy in 5 fractions using the combination of DCA-IMRT. Plans were reviewed and the thirteen cases were compared to plans obtained with optimized automated VMAT based on a set of 28 distinct patients treated with DCA-IMRT who were selected to generate the AP model for the prediction of dose volume constraints. Results Overall, plan quality of DCA-IMRT was superior to AP with VMAT. PTV coverage did not exceed 107% in any case treated with DCA-IMRT, compared to seven patients with VMAT. The median PTV covered by >95% was 98.3% (91.9%–99.7%) with DCA-IMRT, compared to 95.1% (91.5%–97.9%) (p < 0.01) with VMAT. The median mean dose delivered to the treated eye was 22.4 Gy (12.3 Gy–33.3 Gy) with DCA-IMRT compared to 27.2 Gy (15.5 Gy–33.7 Gy) (p < 0.01). Dose to the ipsilateral lacrimal gland and the ipsilateral optic nerve were comparable for DCA-IMRT and VMAT, however, the dose to the lens was lower with DCA-IMRT compared to VMAT. Conclusions The combination of multiple arcs complemented with multiple IMRT fields sets the gold standard for fSRS of ocular melanoma for photon therapy.

Hierarchical enhanced non-rigid registration for target volume correction and propagation for adaptive external beam radiotherapy of carcinoma of the prostate.

Volumes change during fractionated radiotherapy (RT). We investigate a tool based on the Hierarchical Enhanced Registration Algorithm (HERA) to project a 3D segmentation set of the prostate into the subsequent imaging sets at any time point during RT by using intensity‐based image registration techniques. Sequential CT sets during RT at 15, 30, 45, and 60 Gy of two patients were used. Five expert clinicians outlined the prostate in a blinded fashion, defining intraobserver and interobserver variability on a set of 35 and 25 scans, respectively. The observer variability and positioning for manual correction was compared to both affine and elastic image registration‐based contour propagation. The overall mean error of the registration‐based correction of the planning target volume was comparable to the interobserver variability of manual target volume definition. The correction by affine image fusion was inferior to the results of elastic registration. The maximal deviation for the interobserver segmentation was 15.4 mm, 10.5 mm for the affine and 8.0 mm for the elastic registration. The mean interobserver variability was 1.5 (± 1.4) mm, 2.8 (± 2.3) mm for the affine, and 2.2 (± 1.9) mm for the elastic registration. Intensity‐based elastic registration of deformable anatomical structures with HERA is suitable for the assessment of changes of prostate volumes for the purpose of target propagation and adaptive radiotherapy. PACS number: 87.57.nj

PO-0885: Implementation and validation of Pinnacle for stereotactic body radiotherapy with a flattening filter free linac.

Results: The results of the HTT showed an overall three dimensional accuracy of 0.76 mm (SD0.46 mm) for the frameless technique, 0.87mm (SD0.44 mm) for the frame-based technique. The mean 3D setup error of the frameless approach before 6DOF correction was 1.91 mm (SD1.25mm). The rotational errors were larger in the longitudinal direction (0.23° SD0.82°) compared to the lateral (-0.09°SD0.72°) and vertical (-0.10° SD1.03°) ones (p<0.05). The mean 3D intrafraction shift was 0.58 (SD0.42mm) and comparable to frame-based techniques.The intrafractional rotational errors were comparable, 0.01° (SD0.35°), 0.03°(SD0.31°), -0.03° (SD0.33°), for the vertical, longitudinal and lateral, respectively Conclusions: On the basis of phantom studies, the frameless technique showed comparable overall accuracy to the frame-based approach. The immobilization characteristics of the frameless mask approach are comparable to the invasive head ring used during framebased positioning. With proper immobilization and x-ray verification images, frameless radiosurgery can be delivered with high accuracy whilst avoiding the minimal invasiveness offrame-based technique, and can be considered to be a reliable alternative for SRS treatments