Juergen Debus

A Phase II, Randomized, Study of Weekly APG101+Reirradiation versus Reirradiation in Progressive Glioblastoma

Purpose: Preclinical data indicate anti-invasive activity of APG101, a CD95 ligand (CD95L)–binding fusion protein, in glioblastoma. Experimental Design: Patients (N = 91) with glioblastoma at first or second progression were randomized 1:2 between second radiotherapy (rRT; 36 Gy; five times 2 Gy per week) or rRT+APG101 (400 mg weekly i.v.). Patient characteristics [N = 84 (26 patients rRT, 58 patients rRT+APG101)] were balanced. Results: Progression-free survival at 6 months (PFS-6) rates were 3.8% [95% confidence interval (CI), 0.1–19.6] for rRT and 20.7% (95% CI, 11.2–33.4) for rRT+APG101 (P = 0.048). Median PFS was 2.5 (95% CI, 2.3–3.8) months and 4.5 (95% CI, 3.7–5.4) months with a hazard ratio (HR) of 0.49 (95% CI, 0.27–0.88; P = 0.0162) adjusted for tumor size. Cox regression analysis adjusted for tumor size revealed a HR of 0.60 (95% CI, 0.36–1.01; P = 0.0559) for rRT+APG101 for death of any cause. Lower methylation levels at CpG2 in the CD95L promoter in the tumor conferred a stronger risk reduction (HR, 0.19; 95% CI, 0.06–0.58) for treatment with APG101, suggesting a potential biomarker. Conclusions: CD95 pathway inhibition in combination with rRT is an innovative concept with clinical efficacy. It warrants further clinical development. CD95L promoter methylation in the tumor may be developed as a biomarker. Clin Cancer Res; 20(24); 6304–13. ©2014 AACR.

Small molecule receptor tyrosine kinase inhibitor of platelet-derived growth factor signaling (SU9518) modifies radiation response in fibroblasts and endothelial cells

BackgroundSeveral small receptor tyrosine kinase inhibitors (RTKI) have entered clinical cancer trials alone and in combination with radiotherapy or chemotherapy. The inhibitory spectrum of these compounds is often not restricted to a single target. For example Imatinib/Gleevec (primarily a bcr/abl kinase inhibitor) or SU11248 (mainly a VEGFR inhibitor) are also potent inhibitors of PDGFR and other kinases. We showed previously that PDGF signaling inhibition attenuates radiation-induced lung fibrosis in a mouse model. Here we investigate effects of SU9518, a PDGFR inhibitor combined with ionizing radiation in human primary fibroblasts and endothelial cells in vitro, with a view on utilizing RTKI for antifibrotic therapy.MethodsProtein levels of PDGFR-α/-β and phosphorylated PDGFR in fibroblasts were analyzed using western and immunocytochemistry assays. Functional proliferation and clonogenic assays were performed (i) to assess PDGFR-mediated survival and proliferation in fibroblasts and endothelial cells after SU9518 (small molecule inhibitor of PDGF receptor tyrosine kinase); (ii) to test the potency und selectivity of the PDGF RTK inhibitor after stimulation with PDGF isoforms (-AB, -AA, -BB) and VEGF+bFGF. In order to simulate in vivo conditions and to understand the role of radiation-induced paracrine PDGF secretion, co-culture models consisting of fibroblasts and endothelial cells were employed.ResultsIn fibroblasts, radiation markedly activated PDGF signaling as detected by enhanced PDGFR phosphorylation which was potently inhibited by SU9518. In fibroblast clonogenic assay, SU9518 reduced PDGF stimulated fibroblast survival by 57%. Likewise, SU9518 potently inhibited fibroblast and endothelial cell proliferation. In the co-culture model, radiation of endothelial cells and fibroblast cells substantially stimulated proliferation of non irradiated fibroblasts and vice versa. Importantly, the RTK inhibitor significantly inhibited this paracrine radiation-induced fibroblast and endothelial cell activation.ConclusionRadiation-induced autocrine and paracrine PDGF signaling plays an important role in fibroblast and endothelial cell proliferation. SU9518, a PDGFR tyrosine kinase inhibitor, reduces radiation-induced fibroblast and endothelial cell activation. This may explain therapeutic anticancer effects of Imatinib/Gleevec, and at the same time it could open a way of attenuating radiation-induced fibrosis.

Local setup errors in image-guided radiotherapy for head and neck cancer patients immobilized with a custom-made device.

PURPOSEnTo evaluate the local positioning uncertainties during fractionated radiotherapy of head-and-neck cancer patients immobilized using a custom-made fixation device and discuss the effect of possible patient correction strategies for these uncertainties.nnnMETHODS AND MATERIALSnA total of 45 head-and-neck patients underwent regular control computed tomography scanning using an in-room computed tomography scanner. The local and global positioning variations of all patients were evaluated by applying a rigid registration algorithm. One bounding box around the complete target volume and nine local registration boxes containing relevant anatomic structures were introduced. The resulting uncertainties for a stereotactic setup and the deformations referenced to one anatomic local registration box were determined. Local deformations of the patients immobilized using our custom-made device were compared with previously published results. Several patient positioning correction strategies were simulated, and the residual local uncertainties were calculated.nnnRESULTSnThe patient anatomy in the stereotactic setup showed local systematic positioning deviations of 1-4 mm. The deformations referenced to a particular anatomic local registration box were similar to the reported deformations assessed from patients immobilized with commercially available Aquaplast masks. A global correction, including the rotational error compensation, decreased the remaining local translational errors. Depending on the chosen patient positioning strategy, the remaining local uncertainties varied considerably.nnnCONCLUSIONSnLocal deformations in head-and-neck patients occur even if an elaborate, custom-made patient fixation method is used. A rotational error correction decreased the required margins considerably. None of the considered correction strategies achieved perfect alignment. Therefore, weighting of anatomic subregions to obtain the optimal correction vector should be investigated in the future.

Loss of SOX2 expression induces cell motility via vimentin up‐regulation and is an unfavorable risk factor for survival of head and neck squamous cell carcinoma

Recurrent gain on chromosome 3q26 encompassing the gene locus for the transcription factor SOX2 is a frequent event in human squamous cell carcinoma, including head and neck squamous cell carcinoma (HNSCC). Numerous studies demonstrated that SOX2 expression and function is related to distinct aspects of tumor cell pathophysiology. However, the underlying molecular mechanisms are not well understood, and the correlation between SOX2 expression and clinical outcome revealed conflicting data. Transcriptional profiling after silencing of SOX2 expression in a HNSCC cell line identified a set of up‐regulated genes related to cell motility (e.g. VIM, FN1, CDH2). The inverse regulation of SOX2 and aforementioned genes was validated in 18 independent HNSCC cell lines from different anatomical sites. The inhibition of cell migration and invasion by SOX2 was confirmed by constant or conditional gene silencing and accelerated motility of HNSCC cells after SOX2 silencing was partially reverted by down‐regulation of vimentin. In a retrospective study, SOX2 expression was determined by immunohistochemical staining on tissue microarrays containing primary tumor specimens of two independent HNSCC patient cohorts. Low SOX2 expression was found in 19.3% and 44.9% of primary tumor specimens, respectively. Univariate analysis demonstrated a statistically significant correlation between low SOX2 protein levels and reduced progression‐free survival (Cohort I 51 vs. 16 months; Cohort II 33 vs. 12 months) and overall survival (Cohort I 150 vs. 37 months; Cohort II 33 vs. 16 months). Multivariate Cox proportional hazard model analysis confirmed that low SOX2 expression serves as an independent prognostic marker for HNSCC patients. We conclude that SOX2 inhibits tumor cell motility in HNSCC cells and that low SOX2 expression serves as a prognosticator to identify HNSCC patients at high risk for treatment failure.

Accelerated large volume irradiation with dynamic Jaw/Dynamic Couch Helical Tomotherapy

BackgroundHelical Tomotherapy (HT) has unique capacities for the radiotherapy of large and complicated target volumes. Next generation Dynamic Jaw/Dynamic Couch HT delivery promises faster treatments and reduced exposure of organs at risk due to a reduced dose penumbra.MethodsThree challenging clinical situations were chosen for comparison between Regular HT delivery with a field width of 2.5 cm (Reg 2.5) and 5.0 cm (Reg 5.0) and DJDC delivery with a maximum field width of 5.0 cm (DJDC 5.0): Hemithoracic Irradiation, Whole Abdominal Irradiation (WAI) and Total Marrow Irradiation (TMI). For each setting, five CT data sets were chosen, and target coverage, conformity, integral dose, dose exposure of organs at risk (OAR) and treatment time were calculated.ResultsBoth Reg 5.0 and DJDC 5.0 achieved a substantial reduction in treatment time while maintaining similar dose coverage. Treatment time could be reduced from 10:57 min to 3:42 min / 5:10 min (Reg 5.0 / DJDC 5.0) for Hemithoracic Irradiation, from 18:03 min to 8:02 min / 8:03 min for WAI and to 18:25 min / 18:03 min for TMI. In Hemithoracic Irradiation, OAR exposure was identical in all modalities. For WAI, Reg 2.5 resulted in lower exposure of liver and bone. DJDC plans showed a small but significant increase of ∼ 1 Gy to the kidneys, the parotid glans and the thyroid gland. While Reg 5.0 and DJDC were identical in terms of OAR exposure, integral dose was substantially lower with DJDC, caused by a smaller dose penumbra.ConclusionsAlthough not clinically available yet, next generation DJDC HT technique is efficient in improving the treatment time while maintaining comparable plan quality.

Helical intensity-modulated Radiotherapy of the Pelvic Lymph Nodes with Integrated Boost to the Prostate Bed - Initial Results of the PLATIN 3 Trial

BackgroundAdjuvant and salvage radiotherapy of the prostate bed are established treatment options for prostate cancer. While the benefit of an additional radiotherapy of the pelvic lymph nodes is still under debate, the PLATIN 3 prospective phase II clinical trial was initiated to substantiate toxicity data on postoperative IMRT of the pelvic lymph nodes and the prostate bed.MethodsFrom 2009 to 2011, 40 patients with high-risk prostate cancer after prostatectomy with pT3 R0/1xa0M0 or pT2 R1 M0 or a PSA recurrence and eitheru2009>u200920% risk of lymph node involvement and inadequate lymphadenectomy or pNu2009+u2009were enrolled. Patients received two months of antihormonal treatment (AT) before radiotherapy. AT continuation was mandatory during radiotherapy and was recommended for another two years. IMRT of the pelvic lymph nodes (51.0xa0Gy) with a simultaneous integrated boost to the prostate bed (68.0xa0Gy) was performed in 34 fractions. PSA level, prostate-related symptoms and quality of life were assessed at regular intervals for 24xa0months.ResultsOf the 40 patients enrolled, 39 finished treatment as planned. Overall acute toxicity rates were low and no acute grade 3/4 toxicity occurred. Only 22.5% of patients experienced acute grade 2 gastrointestinal (GI) and genitourinary (GU) toxicity. During follow-up, 10.0% late grade 2 GI and 5.0% late grade 2 GU toxicity occurred, and one patient developed late grade 3 proctitis and enteritis. After a median observation time of 24xa0months the PLATIN 3 trial has shown in 97.5% of all patients sufficient safety and thus met its prospectively defined aims. After a median of 24xa0months, 34/38 patients were free of a PSA recurrence.ConclusionsPostoperative whole-pelvis IMRT with an integrated boost to the prostate bed can be performed safely and without excessive toxicity.Trial registrationTrial Numbers: ARO 2009–05, ClinicalTrials.gov: NCT01903408.

Bone density as a marker for local response to radiotherapy of spinal bone metastases in women with breast cancer: a retrospective analysis

BackgroundWe designed this study to quantify the effects of radiotherapy (RT) on bone density as a local response in spinal bone metastases of women with breast cancer and, secondly, to establish bone density as an accurate and reproducible marker for assessment of local response to RT in spinal bone metastases.MethodsWe retrospectively assessed 135 osteolytic spinal metastases in 115 women with metastatic breast cancer treated at our department between January 2000 and January 2012. Primary endpoint was to compare bone density in the bone metastases before, 3xa0months after and 6xa0months after RT. Bone density was measured in Hounsfield units (HU) in computed tomography scans. We calculated mean values in HU and the standard deviation (SD) as a measurement of bone density before, 3xa0months and 6xa0months after RT. T-test was used for statistical analysis of difference in bone density as well as for univariate analysis of prognostic factors for difference in bone density 3 and 6xa0months after RT.ResultsMean bone density was 194.8 HUu2009±u2009SD 123.0 at baseline. Bone density increased significantly by a mean of 145.8 HUu2009±u2009SD 139.4 after 3xa0months (pu2009=u2009.0001) and by 250.3 HUu2009±u2009SD 147.1 after 6xa0months (pu2009<u2009.0001). Women receiving bisphosphonates showed a tendency towards higher increase in bone density in the metastases after 3xa0months (152.6 HUu2009±u2009SD 141.9 vs. 76.0 HUu2009±u2009SD 86.1; pu2009=u2009.069) and pathological fractures before RT were associated with a significantly higher increase in bone density after 3xa0months (202.3 HUu2009±u2009SD 161.9 vs. 130.3 HUu2009±u2009SD 129.2; pu2009=u2009.013). Concomitant chemotherapy (ChT) or endocrine therapy (ET), hormone receptor status, performance score, applied overall RT dose and prescription of a surgical corset did not correlate with a difference in bone density after RT.ConclusionsBone density measurement in HU is a practicable and reproducible method for assessment of local RT response in osteolytic metastases in breast cancer. Our analysis demonstrated an excellent local response within metastases after palliative RT.

Accelerated tomotherapy delivery with TomoEdge technique

TomoEDGE is an advanced delivery form of tomotherapy which uses a dynamic secondary collimator. This plan comparison study describes the new features, their clinical applicability, and their effect on plan quality and treatment speed. For the first 45 patients worldwide that were scheduled for a treatment with TomoEdge, at least two plans were created: one with the previous “standard”mode with static jaws and 2.5 cm field width (Reg 2.5) and one with TomoEdge technique and 5 cm field width (Edge 5). If, after analysis in terms of beam on time, integral dose, dose conformity, and organ at risk sparing the treating physician decided that the Edge 5 plan was not suitable for clinical treatment, a plan with TomoEdge and 2.5 cm field width was created (Edge 2.5) and used for the treatment. Among the 45 cases, 30 were suitable for Edge 5 treatment, including treatments of the head and neck, rectal cancer, anal cancer, malignancies of the chest, breast cancer, and palliative treatments. In these cases, the use of a 5 cm field width reduced beam on time by more than 30% without compromising plan quality. The 5 cm beam could not be clinically applied to treatments of the pelvic lymph nodes for prostate cancer and to head and neck irradiations with extensive involvement of the skull, as dose to critical organs at risk such as bladder (average dose 28 Gy vs. 29 Gy, Reg 2.5 vs. Edge 5), small bowel (29% vs. 31%, Reg 2.5 vs. Edge 5) and brain (average dose partial brain 19 Gy vs. 21 Gy, Reg 2.5 vs. Edge 5) increased to a clinically relevant, yet not statistically significant, amount. TomoEdge is an advantageous extension of the tomotherapy technique that can speed up treatments and thus increase patient comfort and safety in the majority of clinical settings. PACS numbers: 87.55.de, 87.55ne

Survival of women with clear cell and papillary serous endometrial cancer after adjuvant radiotherapy

BackgroundType II (papillary serous and clear cell) endometrial carcinoma (EC) is a rare subgroup and is considered to have an unfavorable prognosis. The purpose of this retrospective analysis was to elucidate the meaning of adjuvant radiotherapy (RT) for clinical outcome and to define prognostic factors in these patients (pts).MethodsFrom 2004-2012 forty-two pts with type II EC underwent surgery followed by adjuvant RT at our department. Median age was 72xa0years. The majority were early stage carcinomas (FIGO I nu2009=u200927 [64.3%], FIGO II nu2009=u20094 [9.5%], FIGO III nu2009=u200911 [26.2%]. Seven pts (16.7%) received adjuvant chemotherapy (ChT). Pts were treated with external beam radiotherapy (EBRT) and brachytherapy (IVB) boost.ResultsFive-year local recurrence free survival (LRFS), distant metastases free survival (DMFS) and overall survival (OS) were 85.4%, 78%, and 64.5% respectively. LRFS was better with lower pT stage, without lymphangiosis (L0), without haemangiosis (V0) and negative resection margins (R0). DMFS was prolonged in lymph node negatives (N0), L0, V0 and R0. OS was improved in younger pts, N0, L0, V0 and after lymphadenectomy (LNE). Multivariate analysis revealed haemangiosis (V1) as the only independent prognostic factor for OS (pu2009=u2009.014) and DMFS (pu2009=u2009.008). For LRFS pT stage remained as an independent prognostic factor (pu2009=u2009.028).ConclusionsAdjuvant RT with EBRT/IVB ensures adequate local control in type II EC, but control rates remain lower than in type I EC. A benefit of additional adjuvant ChT could not be demonstrated and a general omission of EBRT cannot be recommended at this point. Lymphovascular infiltration and pT stage might be the best predictive factors for a benefit from combined local and systemic treatment.

Prognostic factors for survival of women with unstable spinal bone metastases from breast cancer

BackgroundBone metastases are an important clinical issue in women with breast cancer. Particularly, unstable spinal bone metastases (SBM) are a major cause of severe morbidity and reduced quality of life (QoL) due to frequent immobilization. Radiotherapy (RT) is the major treatment modality and is capable of promoting re-ossification and improving stability. Since local therapy response is excellent, survival of these patients with unstable SBM is of high clinical importance. We therefore conducted this analysis to assess survival and to determine prognostic factors for bone survival (BS) in women with breast cancer and unstable SBM.MethodsA total population of 92 women with unstable SBM from breast cancer who were treated with RT at our department between January 2000 and January 2012 was retrospectively investigated. We calculated overall survival (OS) and BS (time between first diagnosis of bone metastases until death) with the Kaplan-Meier method and assessed prognostic factors for BS with a Cox regression model.ResultsMean age at first diagnosis of breast cancer was 60.8xa0yearsu2009±u2009SD 12.4xa0years. OS after 1, 2 and 5xa0years was 84.8, 66.3 and 50xa0%, respectively. BS after 1, 2 and 5xa0years was 62.0, 33.7 and 12xa0%, respectively. An ageu2009>u200950xa0years (pu2009<u2009.001; HR 1.036 [CI 1.015–1.057]), the presence of a single bone metastasis (pu2009=u2009.002; HR 0.469 [CI 0.292–0.753]) and triple negative phenotype (pu2009<u2009.001; HR 1.068 [CI 0.933–1.125]) were identified as independent prognostic factors for BS.ConclusionsOur analysis demonstrated a short survival of women with breast cancer and unstable SBM. Age, presence of a solitary SBM and triple-negative phenotype correlated with survival. Our results may have an impact on therapeutic decisions in the future and offer a rationale for future prospective investigations.