Ilja F. Ciernik

Age as a predictive factor in glioblastomas: population-based study

We evaluated 715 glioblastoma patients diagnosed during 1980–1994 in the Canton of Zurich, Switzerland, to provide information on how patients were treated at the population level. Despite a general policy during the study period of treatment by surgical intervention aimed at maximum tumor removal followed by radiotherapy, there was a marked tendency toward limited treatment with advancing patient age. Of those younger than 65 years, 82% were treated either with surgery followed by radiotherapy, surgery alone or radiotherapy alone, versus 47% of patients 65 years or older. Only 25% of patients older than 75 years underwent surgery and/or radiotherapy, while the remaining patients were given best supportive care (BSC). The mean ages of patients were 54.5 years for those treated with surgery and radiotherapy, 58.3 years for surgery alone, 62.2 years for radiotherapy alone and 69.2 years for BSC. Among patients who were treated with surgery plus radiotherapy and those treated with radiotherapy alone, younger patients (<60 years) had a significantly higher survival rate than older patients (≥60 years). In contrast, no significant difference in survival was observed between younger and older patients treated with surgery alone or receiving BSC, suggesting that lower survival rates in elderly patients with glioblastoma may be at least in part due to a lesser response to radiotherapy.

Patupilone Acts as Radiosensitizing Agent in Multidrug-Resistant Cancer Cells In vitro and In vivo

Interference with microtubule function is a promising antitumoral concept. Paclitaxel is a clinically validated tubulin-targeting agent; however, treatment with paclitaxel is often limited by taxane-related toxicities and is ineffective in tumors with multidrug-resistant cells. Patupilone (EPO906, epothilone B) is a novel non-taxane-related microtubule-stabilizing natural compound that retains full activity in multidrug-resistant tumors and is clinically less toxic than paclitaxel. Here we have investigated the effect of combined treatment with ionizing radiation and patupilone or paclitaxel in the P-glycoprotein-overexpressing, p53-mutated human colon adenocarcinoma cell line SW480 and in murine, genetically defined E1A/ras-transformed paclitaxel-sensitive embryo fibroblasts. Patupilone and paclitaxel alone and in combination with ionizing radiation reduced the proliferative activity of the E1A/ras-transformed cell line with similar potency in the sub and low nanomolar range. SW480 cells were only sensitive to patupilone, and combined treatment with low-dose patupilone (0.1 nmol/L) followed by clinically relevant doses of ionizing radiation (2 and 5 Gy) resulted in a supra-additive cytotoxic effect. Inhibition of the drug efflux protein P-glycoprotein with verapamil resensitized SW480 cells to treatment with low doses of paclitaxel alone and in combination with IR. In tumor xenografts derived from SW480 cells a minimal treatment regimen with patupilone and fractionated irradiation (1 × 2 mg/kg plus 4 × 3 Gy) resulted in an at least additive tumor response with extended tumor growth arrest. Analysis by flow cytometry in vitro revealed an apoptosis- and G2-M-independent mode of radiosensitization by patupilone. Interestingly though, a transient accumulation of cells in S phase was observed on combined treatment.Overall, patupilone might be a promising alternative in paclitaxel-resistant, P-glycoprotein-overexpressing tumors for a combined treatment regimen using ionizing radiation and a microtubule inhibitor.

On-line correction of beam portals in the treatment of prostate cancer using an endorectal balloon device

BACKGROUND Reproducible target volume assessment is required in order to optimize portal field margins in the treatment of prostate cancer. The benefits of an endorectal balloon on target volume assessment remain unclear. MATERIAL AND METHODS Nine patients were treated with a daily placed air filled rectal balloon. Portal films and computer-associated tomography during the treatment were used to determine the position of the structures of interest. Comparative planning with or without a balloon was performed in order to determine rectal wall exposure to radiation. RESULTS The range of movements during treatment predicting the position of the prostate in relation to the symphysis was 0.05-0.59 cm in the lateral direction, 0.27-2.2 cm in the antero-posterior direction, and 0.33-1.8 cm in the crano-caudal direction, as compared to the position of the prostate predicted by the balloon ranging from 0.18 to 0.76 cm in the lateral direction, 0.22-1.68 cm in the antero-posterior direction, and 0.58-2.99 cm in the crano-caudal direction. Planning target volumes (PTV) margins as defined by the position of the balloon were 10 mm in the antero-posterior direction, 6 mm in the lateral direction, and 16 mm in the crano-caudal direction. The volume of rectal wall exposed to radiation was reduced from 40 (+/- 12%) to 25% (+/- 19%) with an endorectal balloon (P < 0.05). CONCLUSIONS Daily online correction with portal vision for external beam set-up is improved by an endorectal balloon device, leading to improved PTV margins and reduced radiation exposure of the rectal wall.

The use of a leg holder immobilisation device in 3D-conformal radiation therapy of prostate cancer.

BACKGROUND AND PURPOSE To evaluate the impact of a leg holder immobilisation device on patient positioning accuracy in the treatment of prostate cancer. MATERIAL AND METHODS Twenty patients of similar age and stage of disease treated with curative external beam radiotherapy for prostate cancer were included prospectively. Ten patients were sequentially allocated to one of the two groups, and treated either with or without a leg holder. Treatment set-up alignment accuracy was assessed with an electronic portal imaging device (EPID). RESULTS Set-up accuracy was 0.3, 0.3 and 0.2 cm for patients with a leg holder, and 0.3, 0.4 and 0.2 cm for patients without a leg holder in the cranio-caudal, anterior-posterior and in the lateral positions, respectively. The difference is not significant. The repositioning accuracy of combined (sagittal and lateral) in-plane rotations on the other hand, was significantly improved with a leg holder device (P = 0.04). CONCLUSIONS Set-up accuracy can be improved using a leg holder immobilisation device in terms of rotational movement accuracy, thus making on-line corrections more accurate using EPID in the treatment of prostate cancer.

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‐

Changing PET/CT manifestation of neurolymphomatosis

Neurolymphomatosis (NL) is a rare manifestation of lymphoma [1]. CT and MRI have been used to detect NL, to stage the extent of the nerve involvement and to guide biopsy. Recent reports have demonstrated the value of FDG-PET/CT in patients with NL [2–4]. Here we present the FDG-PET/CT imaging follow-up of a 56-yearold patient with diffuse large B-cell lymphoma initially presenting as stage IE involving the urinary bladder and presacral area. After six cycles of chemotherapy and pelvic radiation therapy, a complete response was documented. However, there was relapse of the lymphoma, restricted to neural structures. In a–c the PET/CT images demonstrate increased FDG uptake in the cranial nerves, delineated on fused axial images [b, gasserian ganglion of the trigeminal nerve (arrows) and c the cervical and lumbar nerve roots (arrows)]. The patient was treated with high-dose methotrexate and subsequent radiation therapy. Six weeks after the end of radiation therapy, progressive NL (d–f) in the brachial (e, arrows) and lumbosacral plexus (f, arrows) was observed. Because in NL nerve biopsies may fail and MRI may not be sufficiently sensitive to show the entire extent of nerve involvement, FDG-PET/CT with whole-body imaging and exact anatomical correlation is useful in staging, biopsy guidance, treatment planning and therapy assessment [5].

CD4+ CD25+ treg regulate the contribution of CD8+ T-cell subsets in repopulation of the lymphopenic environment

Peripheral T‐cell expansion is of major relevance for immune function after lymphopenia. In order to promote regeneration, the process should result in a peripheral T‐cell pool with a similar subpopulation structure as before lymphopenia. We investigated the repopulation of the CD8+ central‐memory T cells (TCM) and effector‐memory T cells (TEM) pools after adoptive transfer of sorted CD8+ T cells from naïve, TCM and TEM subsets into T‐cell‐deficient hosts. We show that the initial kinetics of expansion are distinct for each subset and that the contribution to the repopulation of the CD8+ T‐cell pool by the progeny of each subset is not a mere function of its initial expansion. We demonstrate that CD4+CD25+ Treg play a major role in the repopulation of the CD8+ T‐cell pool and that CD8+ T‐cell subsets impact on each other. In the absence of CD4+CD25+ Treg, a small fraction of naïve CD8+ T cells strongly proliferates, correlating with further expansion and differentiation of co‐expanding CD8+ T cells. CD4+CD25+ Treg suppress these responses and lead to controlled repopulation, contributing decisively to the maintenance of recovered TCM and TEM fractions, and leading to repopulation of each pool with progeny of its own kind.

External beam radiotherapy for unresectable hepatocellular carcinoma, an international multicenter phase I trial, SAKK 77/07 and SASL 26

PurposeTo assess feasibility and safety of conventionally fractionated radiotherapy (cfRT) in patients with hepatocellular carcinoma (HCC).MethodsPatients with histologically confirmed stage cT1-4, cN0-1 HCC and Child-Pugh Score (CPS) A or B disease were included in a phase I multicenter trial. Metastatic HCC were allowed if ≥90% of total tumor volume was located within the liver. Patients were enrolled onto five dose-escalation levels (54–70Gy in 2Gy fractions) based on a modified 3 + 3 design, with cohorts of five patients instead of three patients in dose levels 4 and 5. Primary trial endpoint was dose-limiting toxicity (DLT), as specifically defined for 17 clinical and nine laboratory parameters as grade ≥3 or ≥4 toxicity (CTCAE vs. 3). The threshold to declare a dose level as maximum tolerated dose (MTD) was defined as a DLT rate of ≤16.7% in dose levels 1–3, and ≤10% in dose levels 4–5. Best objective response of target liver lesions and adverse events (AE’s) were assessed as secondary endpoints.ResultsThe trial was terminated early in DL 3 due to low accrual. Nineteen patients were recruited. Fifteen patients were evaluable for the primary and 18 for the secondary endpoints. Maximum tolerated dose was not reached. One patient in dose level 1, and one patient in dose level 2 experienced DLT (lipase > 5xULN, and neutrophils <500/μL respectively). However, dose level 3 (62Gy) was completed, with no DLTs in 3 patients.Overall, 56% of patients had a partial response and 28% showed stable disease according to RECIST. No signs of radiation induced liver disease (RILD). Two patients in dose level 3 experienced lymphocytopenia grade 4, with no clinical impact.ConclusionConventionally fractionated radiotherapy of 58Gy to even large HCC was safe for patients with CPS A and B. 62Gy was delivered to three patients without any sign of clinically relevant increased toxicity. The maximum tolerated dose could not be determined.Trial registrationClinicalTrials.gov identifier NCT00777894, registered October 21st, 2008.

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