Purpose/Objective(s)Multimodal approaches integrating EGFR signaling inhibitors into chemoradiotherapy regimens seem to be beneficial for patients with locally advanced pancreatic cancer. Nevertheless many of these patients die within the first year after diagnosis partially due to EGFR targeted therapy escape mechanisms. It would be of interest to identify this unfavorable prognosis group early within the therapy-course in order to either escalate or deescalate therapy regimens.Materials/MethodsThirty-eight patients with locally advanced pancreatic cancer received 54/45 Gy in IMRT technique in combination with Gemcitabine and Cetuximab (400 mg/m2 as initial dose1 week before CRT followed by 250 mg/m2/week). Blood samples were obtained before Cetuximab (d0), after Cetuximab but before CRT (d8), 2 weeks within the CRT (d24) and at restaging (d70). Whole blood transcriptomics were performed after total RNA isolation and depletion of globin mRNA using Agilent's human genome wide oligo microarray platform. To identify differentially regulated genes for the endpoint "survival cut-off 12 months," two class t tests were performed for the intervals d0-d8, d8-d24, and d8-d70. Gene Ontology (GO)-term analysis was applied to the selected genes. Plasma protein levels of interleukins (IL-2, IL-6, IL-8, IL-10, IL-12) were measured using the FastQuant (sandwich antibody) system. Multivariate Cox Regression Analysis was used to identify prognostic markers.ResultsHigh plasma protein levels of IL-12 and low levels of IL-10 1 week after Cetuximab were associated with longer survival (p = 0.004 and p = 0.04). Transcriptomics confirmed these findings, suggesting that an enhanced anti-tumorimmunity expressed in IL-12 and IL-10 pathways is linked to longer survival. Although plasma protein IL-6 levels after Cetuximab could not be linked to survival, a strong correlation was found for IL-6 regulations in the GO-term analysis and survival: Patients surviving less than 12 months had a dramatically positive IL-6 production upregulation at d8 (p = 0.5, 8E-005). These IL-6 related GO Terms were significantly regulated in the same manner for the d8-d24 and d8-d70 intervals. Further, plasma protein regulations within the first weeks of CRT (d8-d24) showed that low levels of IL-2 and IL-8 were associated with longer survival (p = 0.05 and p = 0.02).ConclusionsImmune regulations play an important part in the therapy response of pancreatic cancer patients to radiotherapy and Cetuximab. Our findings suggest the existence of an IL-6 mediated escape mechanism to anti-EGFR therapy, which was identified by transcriptomics but not by plasma protein measurements as early as one week after the first infusion of Cetuximab. In these patients additional anti-IL-6 Therapy might be a beneficial approach. Purpose/Objective(s)Multimodal approaches integrating EGFR signaling inhibitors into chemoradiotherapy regimens seem to be beneficial for patients with locally advanced pancreatic cancer. Nevertheless many of these patients die within the first year after diagnosis partially due to EGFR targeted therapy escape mechanisms. It would be of interest to identify this unfavorable prognosis group early within the therapy-course in order to either escalate or deescalate therapy regimens. Multimodal approaches integrating EGFR signaling inhibitors into chemoradiotherapy regimens seem to be beneficial for patients with locally advanced pancreatic cancer. Nevertheless many of these patients die within the first year after diagnosis partially due to EGFR targeted therapy escape mechanisms. It would be of interest to identify this unfavorable prognosis group early within the therapy-course in order to either escalate or deescalate therapy regimens. Materials/MethodsThirty-eight patients with locally advanced pancreatic cancer received 54/45 Gy in IMRT technique in combination with Gemcitabine and Cetuximab (400 mg/m2 as initial dose1 week before CRT followed by 250 mg/m2/week). Blood samples were obtained before Cetuximab (d0), after Cetuximab but before CRT (d8), 2 weeks within the CRT (d24) and at restaging (d70). Whole blood transcriptomics were performed after total RNA isolation and depletion of globin mRNA using Agilent's human genome wide oligo microarray platform. To identify differentially regulated genes for the endpoint "survival cut-off 12 months," two class t tests were performed for the intervals d0-d8, d8-d24, and d8-d70. Gene Ontology (GO)-term analysis was applied to the selected genes. Plasma protein levels of interleukins (IL-2, IL-6, IL-8, IL-10, IL-12) were measured using the FastQuant (sandwich antibody) system. Multivariate Cox Regression Analysis was used to identify prognostic markers. Thirty-eight patients with locally advanced pancreatic cancer received 54/45 Gy in IMRT technique in combination with Gemcitabine and Cetuximab (400 mg/m2 as initial dose1 week before CRT followed by 250 mg/m2/week). Blood samples were obtained before Cetuximab (d0), after Cetuximab but before CRT (d8), 2 weeks within the CRT (d24) and at restaging (d70). Whole blood transcriptomics were performed after total RNA isolation and depletion of globin mRNA using Agilent's human genome wide oligo microarray platform. To identify differentially regulated genes for the endpoint "survival cut-off 12 months," two class t tests were performed for the intervals d0-d8, d8-d24, and d8-d70. Gene Ontology (GO)-term analysis was applied to the selected genes. Plasma protein levels of interleukins (IL-2, IL-6, IL-8, IL-10, IL-12) were measured using the FastQuant (sandwich antibody) system. Multivariate Cox Regression Analysis was used to identify prognostic markers. ResultsHigh plasma protein levels of IL-12 and low levels of IL-10 1 week after Cetuximab were associated with longer survival (p = 0.004 and p = 0.04). Transcriptomics confirmed these findings, suggesting that an enhanced anti-tumorimmunity expressed in IL-12 and IL-10 pathways is linked to longer survival. Although plasma protein IL-6 levels after Cetuximab could not be linked to survival, a strong correlation was found for IL-6 regulations in the GO-term analysis and survival: Patients surviving less than 12 months had a dramatically positive IL-6 production upregulation at d8 (p = 0.5, 8E-005). These IL-6 related GO Terms were significantly regulated in the same manner for the d8-d24 and d8-d70 intervals. Further, plasma protein regulations within the first weeks of CRT (d8-d24) showed that low levels of IL-2 and IL-8 were associated with longer survival (p = 0.05 and p = 0.02). High plasma protein levels of IL-12 and low levels of IL-10 1 week after Cetuximab were associated with longer survival (p = 0.004 and p = 0.04). Transcriptomics confirmed these findings, suggesting that an enhanced anti-tumorimmunity expressed in IL-12 and IL-10 pathways is linked to longer survival. Although plasma protein IL-6 levels after Cetuximab could not be linked to survival, a strong correlation was found for IL-6 regulations in the GO-term analysis and survival: Patients surviving less than 12 months had a dramatically positive IL-6 production upregulation at d8 (p = 0.5, 8E-005). These IL-6 related GO Terms were significantly regulated in the same manner for the d8-d24 and d8-d70 intervals. Further, plasma protein regulations within the first weeks of CRT (d8-d24) showed that low levels of IL-2 and IL-8 were associated with longer survival (p = 0.05 and p = 0.02). ConclusionsImmune regulations play an important part in the therapy response of pancreatic cancer patients to radiotherapy and Cetuximab. Our findings suggest the existence of an IL-6 mediated escape mechanism to anti-EGFR therapy, which was identified by transcriptomics but not by plasma protein measurements as early as one week after the first infusion of Cetuximab. In these patients additional anti-IL-6 Therapy might be a beneficial approach. Immune regulations play an important part in the therapy response of pancreatic cancer patients to radiotherapy and Cetuximab. Our findings suggest the existence of an IL-6 mediated escape mechanism to anti-EGFR therapy, which was identified by transcriptomics but not by plasma protein measurements as early as one week after the first infusion of Cetuximab. In these patients additional anti-IL-6 Therapy might be a beneficial approach.

To report our experience with EBRT after marginal or incomplete resection in patients suffering from desmoid tumors. We retrospectively analyzed 43 pts (m:f 18:25) with desmoid tumors treated by EBRT at our institution. Median age was 38 years (18 - 69) and median tumor size was 10 cm (3 - 30). 22 pts suffered from extremity tumors, whereas 21 showed tumors located in trunk, neck or abdominal cavity. 24 pts had at least one previous surgical resection before the current treatment (17 same location, 3 different location, 4 both). Surgery resulted in close margins (< 5mm) in 5 pts, microscopic residual disease in 23 and macroscopic residual disease in 10, whereas 5 pts had currently no surgery at all. EBRT was carried out with a median dose of 50 Gy (32 - 60) in conventional fractionation. The median follow up was 72 months (range 2 to 255). 11 pts (26%) developed local recurrences after a median time of 22 months (7 - 77), transferring into actuarial 5- and 10-year local control rates of 69% and 65%. Univariate subgroup analyses revealed no differences in local control according to resection margin (R0/1 vs R2/no surgery), gender, primary vs. recurrent local situation or size. A trend to improved local control was observed in patients of advanced age. The impact of radiation dose on local control was analyzed for different cutoff points (40 Gy, 45 Gy, 50 Gy, 54 Gy). A statistically significant difference in local control was observed only for a cutoff dose of 45 Gy (10-year LC <45 Gy: 44% vs ≥45 Gy: 72%, p = 0.05), although patients with doses ≥54 Gy showed the highest local control (10-year LC 81%). Acute grade 2 toxicity was observed as radiation dermatitis in 7 pts (13%). All of them had been treated with doses ≥ 50 Gy (grade 2 toxicity rate ≥50 Gy : 25%, ≥54 Gy : 30%). Three patients (7%) developed grade ≥2 late toxicity as lymph edema, all of them had been treated with doses ≥ 50 Gy. 5 pts (11%) developed new desmoids clearly outside the treated region with locally controlled disease until end of f/u after a median time of 16 months (8 - 66), resulting in 5- and 10-year overall PFS rates of 57% and 49%. Patients with previous surgery for desmoids at a different location had a statistically significant increased risk for progression outside the treated area (p = 0.016). If those patients were excluded from analysis, the 5-year and 10-year overall PFS rates increased to 66% and 56%. EBRT of desmoid tumors after marginal or incomplete resection resulted in long term local control in about two thirds of the patients regardless of resection margin. Dose escalation (≥ 45 Gy) resulted in significant improved local control but has to be balanced against increased risks for toxicity. Patients with previous involvement of different regions showed an increased risk of failure outside the treated area.

Christoph Reissfelder (christoph.reissfelder@med.uni-heidelberg.de) Carmen Timke (c.timke@dkfz.de) Hubertus Schmitz-Winnenthal (hubertus.schmitz-winnenthal@med.uni-heidelberg.de) Nuh N Rahbari (nuh.rahbari@med.uni-heidelberg.de) Moritz Koch (moritz.koch@med.uni-heidelberg.de) Felix Klug (f.klug@dkfz.de) Falk Roeder (f.roeder@dkfz.de) Jürgen Debus (juergen.debus@med.uni-heidelberg.de) Markus W Buechler (markus.buechler@med.uni-heidelberg.de) Philipp Beckhove (p.beckhove@dkfz.de) Peter E Huber (p.huber@dkfz.de) Juergen Weitz (juergen.weitz@med.uni-heidelberg.de)

Abstract Objective: Despite progress in understanding molecular changes in glioblastoma multiforme (GBM), it remains a cancer with poor prognosis in need of better therapy. Pathological features of GBM are explosive growth, angiogenesis and its unique diffuse, infiltrative growth pattern. There is a consensus that cell-matrix-interactions play a pivotal role for infiltrative growth. Connective tissue growth factor (CTGF) is a matricellular protein that is involved in many pathological processes including tumorigenesis and invasion. CTGF modulates cell-matrix-interactions that may allow glioma cells to invade brain parenchyma, degrade the extracellular matrix (ECM), and enhance proliferation and angiogenesis in GBM. High CTGF-expression levels have been reported to correlate with tumor grade, invasiveness and poor patient survival. Here the effects of a human monoclonal anti-CTGF-antibody (FG-3019) were investigated alone and in combination with irradiation in vitro and in vivo in an orthotopic glioma model in mice. Methods and materials: In vitro studies were performed with two established human glioma cell lines, U87MG and T98G, as well as with primary isolated human glioblastoma cancer stem-like cells (CSLCs) cells. The effects of FG-3019 alone and in combination with photon irradiation (6 MV Linac) on clonogenic survival, proliferation, migration, neurosphere formation, and limiting dilution were determined. RNA was isolated from CSLCs and gene expression changes were examined after different treatments using micro-arrays and RT-PCR. In vivo, CSLCs were subcultured as neurospheres and stereotactically implanted into brains of SCID-beige mice. Mice brains were treated with 7Gy single dose radiation +/− FG-3019. The treatment effects were assessed by MRI, survival time and histology. Results: Tumor growth delay in the orthotopic tumor model resulted from treatment with radiation or FG-3019 alone, which was significantly enhanced by combined treatment. Similarly, animal survival was prolonged by each monotherapy and significantly enhanced by the combination. Histology showed that FG-3019 significantly reduced constitutive and radiation-induced tumor invasion into the brain parenchyma. FG-3019 also reduced intracellular CTGF expression, glioma cell proliferation, deposition of different types of collagen and reduced microvessel density. FG-3019 also reduced expression of Nestin and the stem cell marker SOX-2. In vitro, FG-3019 and irradiation reduced clonogenicity, proliferation and migration of U87MG, T98G and CSLCs, which was enhanced by the combination. Gene expression analysis revealed that FG-3019 down regulated tumorigenesis- and tumor-invasion-related genes. Conclusions: The human monoclonal CTGF antibody, FG-3019, shows remarkable anti-tumorigenic and anti-invasive effects in vitro and in vivo in a primary human glioblastoma model growing orthotopically in mice. Our results indicate that FG-3019 alone and in combination with radiotherapy is a promising approach for clinical translation in humans. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B206.

Motion-adapted radiotherapy requires dedicated four-dimensional imaging techniques. The objective was to investigate three-dimensional pancreatic tumor motion by means of time resolved magnetic resonance imaging (4D-MRI). Seven patients with resectable pancreatic cancer were enrolled in a prospective internal ethics committee-approved study and examined during shallow free-breathing using dynamic multislice 2D balanced SSFP (TrueFISP) sequences at 1,5T MRI. Images were acquired in coronal and axial orientation to evaluate motion along craniocaudal (cc)-, anterior-posterior (ap)- and right-left (rl)-axis. 2.8 frames/s were obtained over an acquisition time of 110 s for axial and 90 s for coronal sequence. In a retrospective data analysis, tumor motion was quantified semi automatically using an in-house developed dedicated software. The correlation between tumor and diaphragm motion was assessed using a Pearson-correlation test. A mean of 28 (range, 14 - 45) consecutive breathing cycles in the axial sequence and 21 (range, 9 - 37) in the coronal sequence were recorded respectively. This corresponds to a mean breathing frequency of 14 cycles/min (range, 7 - 22). The respiratory-induced mean cranio-caudal (cc) displacement of the tumor was 11 ± 5.3 (SD) mm (range, 3.9 - 21,5). The mean antero-posterior displacement was 8.7 ± 4.0 (SD) mm (range, 2.9 - 13.4), while mean right-left movement was 5.1 ± 2.6 (SD) mm (range, 0.7 - 9.4). The mean amplitude of diaphragm motion in the cc dimension was 12 ± 6.9 (SD) mm (range, 3.1 - 25.9). The tumor motion correlated remarkably with the diaphragm motion regarding both breathing amplitude (r = 0.83 ± 0.08 SD) and frequency (r = 0.68 ± 0.11 SD). Dynamic MRI is an excellent tool for non-invasive real-time imaging of pancreatic tumor motion, allowing for repeated and prolonged measurements without radiation exposure. Motion of pancreatic tumors is quite variable between patients but correlates well with diaphragmatic motion. Therefore, 4D-MRI appears to be suitable for patient selection in motion adapted radiotherapy.

Pancreatic stellate cells have been investigated mostly for their activation process, supposed to support the development of pancreatic disease. Few studies have been presented on reversal of the activation process in vitro. Thiazolidinediones (TZDs) have been used as antidiabetics and have now been reported to exert antifibrotic activity. We tested effects of natural and synthetic ligands of peroxisome proliferator-activated receptor gamma (PPARγ) on human pancreatic fibroblastoid cells (hPFCs) in search for specificity of action. Ciglitazone, as a prototype of TZDs, was shown to have reversible growth inhibitory effects on human pancreatic fibroblastoid cells/stellate cells. Cells treated with ciglitazone for three days showed enhanced lipid content and induction of proteins involved in lipid metabolism. Collagen synthesis was reduced in hPFC. Interaction of PPARγ with DNA binding sites upon ligand binding was shown by gel shift analysis. These findings point toward a potential for adipocyte differentiation in human pancreatic fibroblastoid cells.

Connective tissue growth factor (CTGF) is a matricellular protein that is a central mediator of tissue remodeling. CTGF expression is elevated in patients with idiopathic pulmonary fibrosis. Several studies in different organs have suggested that CTGF is essential for sustained fibrosis. Therefore, inhibition of CTGF may be therapeutically beneficial to fibrosis patients. Radiation induced lung fibrosis is a dose limiting side effect. Here we investigated this concept in a murine model of radiation induced lung fibrosis. Pulmonary fibrosis was initiated with a single, full thorax irradiation (20 Gy) to 6 groups of 25 mice. One group of mice remained untreated, while the other 5 groups received 8 weeks of control human IgG or an anti-CTGF monoclonal antibody (FG-3019). Administration of FG-3019 began 2 days before or after irradiation, or 20 days, or 16 weeks after irradiation. Two additional groups were not irradiated, but received 8 weeks of human IgG or FG-3019. Lung density of all surviving mice was monitored by computed tomography (CT). 30 weeks after irradiation, oxygen saturation was determined by blood gas analysis of surviving mice. All groups receiving FG-3019 exhibited better survival than irradiated, untreated groups, with the 20-day group demonstrating the best survival. Histological examination demonstrated that significant lung remodeling occurred between 13 and 19 weeks after irradiation. FG-3019 attenuated this remodeling in a schedule-dependent manner, with the 20-day group exhibiting the least remodeling. Increased lung densities observed between 22 and 31 weeks after irradiation were attenuated by FG-3019 beginning 2 days before or after irradiation. Administration of FG-3019 beginning 20 days or 16 weeks after irradiation had also a beneficial effect on lung densities, with a sustained effect after cessation of the drug administration. Since the lung density in the 16-week group had already increased at the time that drug administration began, achieving normal lung density required reversal of the radiation-induced changes. Comparison of oxygen saturation with lung density at 30 weeks demonstrated a good correlation and suggested that reduction in lung density is a good surrogate for improvement in lung function. The anti-CTGF monoclonal antibody FG-3019 can attenuate radiation induced lung fibrosis and reverses established fibrosis, improves lung function, and increases the survival of mice. The data support further research on the role of CTGF in radiation response in general and may suggest a clinical evaluation of blocking CTGF signaling as a new concept for preventing radiation induced lung injury.

Combination of targeted drugs is considered as one possibility for improving the therapeutic index in cancer therapy. However, it is far from obvious which targeted drugs can favorably be combined. Combining radiotherapy with either the EGFR antibody Cetuximab or the small molecule integrin inhibitor Cilengitide in dual combinations has shown promise in preclinical and clinical settings. We analyzed the therapeutic potential of combining all three modalities in a human pancreatic cancer model in vitro and in vivo. Human dermal microvascular endothelial (HDMEC) and BXPC3 human pancreatic cancer cells were exposed to Cilengitide, Cetuximab and radiation alone and in dual and triple combinations with various concentrations and doses. In vitro, proliferation, migration/invasion, clonogenic and tube formation assays were performed and apoptosis was measured by FACS. Genome wide transcriptomics (44k Agilent platform) was performed along with qRT-PCR and Western for protein analysis. In vivo, in a s.c. BXPC3 model in balb c nude mice the effects of mono, dual and triple treatments with concurrent radiation (5x2Gy) were analyzed in 8 groups by tumor growth, histology and imaging using MRI, CT, and US. We found that in vitro and in vivo (e.g. tumor growth delay), the anti-endothelial and anti-tumor effects of the triple combination consisting of Cetuximab, Cilengitide and radiation was superior to dual combinations, while dual combinations were superior to monotherapies. The superiority was evident in cell proliferation, migration, tube formation, clonogenic survival, and apoptosis assays. Supra-additivity was found in isobologram analyses for the Cilengitide and Cetuximab combination in proliferation and clonogenic assays as well as for reducing tumor growth in vivo. Exploring the underlying signaling mechanisms, we found by transcriptomics in vitro that the Cilengitide drug target (integrinbetaV) is upregulated by radiation and Cetuximab, which was confirmed by IHC in vivo. Moreover, Cetuximab suppressed the Cilengitide and radiation induced upregulation of VEGF signaling. The strong antiangiogenic effects of the triple combination with a short period of transient vessel normalization in vivo was evident in SMA/CD31 IHC along with corresponding perfusion analyses of contrast enhanced MRI/CT and US imaging. Our data suggest that Cilengitide and Cetuximab can favorably be combined in dual combinations and in a triple combination with radiotherapy in a human pancreatic cancer model. The combinatorial benefits can be explained in part in terms of the underlying signaling mechanisms. Clinical translation for pancreatic carcinoma seems feasible due to the clinical availability of all modalities.

Purpose/Objective(s)The value of intensity-modulated radiotherapy (IMRT) as part of a trimodal therapy of malignant pleural mesothelioma (MPM) is still unclear, especially as significant toxicity to the contralateral lung was reported by several institutions. Here we report on the clinical results of patients with MPM treated in Heidelberg with a trimodal therapy consisting of chemotherapy (CX), extrapleural pneumectomy (EPP) and IMRT in terms of treatment toxicity, tumor control rates, and survival.Materials/MethodsStarting in 2003, 47 patients with MPM were treated with trimodal therapy in Heidelberg. The patients received an induction CX, usually consisting of 3 cycles Cisplatin/Pemetrexed or Cisplatin/Gemcitabine. Then they underwent EPP, including removal of the complete afflicted lung together with parietal pleura, pericardium, and diaphragm. No macroscopic tumor was left. Then the operated hemithorax was irradiated with IMRT for optimal target coverage while sparing the organs at risk like liver, kidneys, heart, contralateral lung, and spinal cord. Median target dose was 50-54 Gy in 2 Gy fractions. Patient positioning was verified by an in-room CT scanner at least once per week. Patient aftercare was performed every 3 months and included a CT scan of the thorax.ResultsForty-one patients could complete the therapy as planned and were included in the outcome analysis. The other 6 patients had to abort the RT course early because of non-RT-related events. Mean dose to the contralateral lung could be kept below 7 Gy in most cases. Common adverse effects of the IMRT were low-grade (CTC°I-II) skin erythema, nausea, and fatigue. Median follow-up time from start of RT was 12 months (range, 2-66 months). One patient showed clinical symptoms of pneumonitis and fully recovered after steroid therapy (mean dose to contralateral lung in this case was 11 Gy). No higher-grade radiation-induced side effects were observed. 2-yrs local control since the beginning of RT was 62% and 2-yrs progression free survival 33%. Median overall survival since the beginning of RT was 22 months.ConclusionsTumor control and survival rates are comparable to results reported by other institutions. The IMRT was well tolerated, especially no higher-grade radiation-induced pneumonitis was observed. Compared to the literature, these results suggest a critical dose-response relationship for the contralateral lung after EPP between mean doses of approx. 5 to 15 Gy. Advanced IMRT combined with image-guided application allow staying at the lower end of this range, so trimodal therapy with IMRT remains a promising treatment option for eligible MPM patients, which should be further evaluated in randomized clinical trials. Purpose/Objective(s)The value of intensity-modulated radiotherapy (IMRT) as part of a trimodal therapy of malignant pleural mesothelioma (MPM) is still unclear, especially as significant toxicity to the contralateral lung was reported by several institutions. Here we report on the clinical results of patients with MPM treated in Heidelberg with a trimodal therapy consisting of chemotherapy (CX), extrapleural pneumectomy (EPP) and IMRT in terms of treatment toxicity, tumor control rates, and survival. The value of intensity-modulated radiotherapy (IMRT) as part of a trimodal therapy of malignant pleural mesothelioma (MPM) is still unclear, especially as significant toxicity to the contralateral lung was reported by several institutions. Here we report on the clinical results of patients with MPM treated in Heidelberg with a trimodal therapy consisting of chemotherapy (CX), extrapleural pneumectomy (EPP) and IMRT in terms of treatment toxicity, tumor control rates, and survival. Materials/MethodsStarting in 2003, 47 patients with MPM were treated with trimodal therapy in Heidelberg. The patients received an induction CX, usually consisting of 3 cycles Cisplatin/Pemetrexed or Cisplatin/Gemcitabine. Then they underwent EPP, including removal of the complete afflicted lung together with parietal pleura, pericardium, and diaphragm. No macroscopic tumor was left. Then the operated hemithorax was irradiated with IMRT for optimal target coverage while sparing the organs at risk like liver, kidneys, heart, contralateral lung, and spinal cord. Median target dose was 50-54 Gy in 2 Gy fractions. Patient positioning was verified by an in-room CT scanner at least once per week. Patient aftercare was performed every 3 months and included a CT scan of the thorax. Starting in 2003, 47 patients with MPM were treated with trimodal therapy in Heidelberg. The patients received an induction CX, usually consisting of 3 cycles Cisplatin/Pemetrexed or Cisplatin/Gemcitabine. Then they underwent EPP, including removal of the complete afflicted lung together with parietal pleura, pericardium, and diaphragm. No macroscopic tumor was left. Then the operated hemithorax was irradiated with IMRT for optimal target coverage while sparing the organs at risk like liver, kidneys, heart, contralateral lung, and spinal cord. Median target dose was 50-54 Gy in 2 Gy fractions. Patient positioning was verified by an in-room CT scanner at least once per week. Patient aftercare was performed every 3 months and included a CT scan of the thorax. ResultsForty-one patients could complete the therapy as planned and were included in the outcome analysis. The other 6 patients had to abort the RT course early because of non-RT-related events. Mean dose to the contralateral lung could be kept below 7 Gy in most cases. Common adverse effects of the IMRT were low-grade (CTC°I-II) skin erythema, nausea, and fatigue. Median follow-up time from start of RT was 12 months (range, 2-66 months). One patient showed clinical symptoms of pneumonitis and fully recovered after steroid therapy (mean dose to contralateral lung in this case was 11 Gy). No higher-grade radiation-induced side effects were observed. 2-yrs local control since the beginning of RT was 62% and 2-yrs progression free survival 33%. Median overall survival since the beginning of RT was 22 months. Forty-one patients could complete the therapy as planned and were included in the outcome analysis. The other 6 patients had to abort the RT course early because of non-RT-related events. Mean dose to the contralateral lung could be kept below 7 Gy in most cases. Common adverse effects of the IMRT were low-grade (CTC°I-II) skin erythema, nausea, and fatigue. Median follow-up time from start of RT was 12 months (range, 2-66 months). One patient showed clinical symptoms of pneumonitis and fully recovered after steroid therapy (mean dose to contralateral lung in this case was 11 Gy). No higher-grade radiation-induced side effects were observed. 2-yrs local control since the beginning of RT was 62% and 2-yrs progression free survival 33%. Median overall survival since the beginning of RT was 22 months. ConclusionsTumor control and survival rates are comparable to results reported by other institutions. The IMRT was well tolerated, especially no higher-grade radiation-induced pneumonitis was observed. Compared to the literature, these results suggest a critical dose-response relationship for the contralateral lung after EPP between mean doses of approx. 5 to 15 Gy. Advanced IMRT combined with image-guided application allow staying at the lower end of this range, so trimodal therapy with IMRT remains a promising treatment option for eligible MPM patients, which should be further evaluated in randomized clinical trials. Tumor control and survival rates are comparable to results reported by other institutions. The IMRT was well tolerated, especially no higher-grade radiation-induced pneumonitis was observed. Compared to the literature, these results suggest a critical dose-response relationship for the contralateral lung after EPP between mean doses of approx. 5 to 15 Gy. Advanced IMRT combined with image-guided application allow staying at the lower end of this range, so trimodal therapy with IMRT remains a promising treatment option for eligible MPM patients, which should be further evaluated in randomized clinical trials.