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When Roentgen discovered the X-rays 125 years ago, his finding was soon recognized as a breakthrough in research and awarded with the Nobel Prize. Today X-rays are widely used in natural and applied sciences and even art. In medicine, X-rays have made an impressive impact far beyond their original domain of diagnostic imaging. In cancer treatment, X-rays are indispensable for reaching the goal of uncomplicated and lasting tumor control. Using the possibilities of modern technology and the innovative mind of physicians and physicists, definitive cancer cure cannot only be achieved by combination of surgery and radiation, but also by radiotherapy alone. One prominent example is the application of single high radiation doses with optimal geometrical precision through image-guided stereotactic radiotherapy. The article aims to highlight past, current, and future sustainable developments in oncology in general, but in radiation oncology, especially. We discuss the very complex challenge of generating evidence by clinical research. In this context, the tumor registries play a very important role. The data of tumor registries and the results of clinical studies demonstrate the benefit for cancer patients who experienced individualized radiotherapy. For cancer cure, it is most important to treat in an early, localized stage of the disease.

Aim To report long-term data regarding biochemical control and late toxicity of simultaneous integrated boost intensity modulated radiotherapy (SIB-IMRT) with tomotherapy in patients with localized prostate cancer. Background Dose escalation improves cancer control after curative intended radiation therapy (RT) to patients with localized prostate cancer, without increasing toxicity, if IMRT is used. Materials and methods In this retrospective analysis, we evaluated long-term toxicity and biochemical control of the first 40 patients with intermediate risk prostate cancer receiving SIB-IMRT. Primary target volume (PTV) 1 including the prostate and proximal third of the seminal vesicles with safety margins was treated with 70 Gy in 35 fractions. PTV 2 containing the prostate with smaller safety margins was treated as SIB to a total dose of 76 Gy with 2.17 Gy per fraction. Toxicity was evaluated using an adapted CTCAE-Score (Version 3). Results Median follow-up of living patients was 66 (20–78) months. No late genitourinary toxicity higher than grade 2 has been reported. Grade 2 genitourinary toxicity rates decreased from 58% at the end of the treatment to 10% at 60 months. Late gastrointestinal (GI) toxicity was also moderate, though the prescribed PTV Dose of 76 Gy was accepted at the anterior rectal wall. 74% of patients reported any GI toxicity during follow up and no toxicity rates higher than grade 2 were observed. Grade 2 side effects were reported by 13% of the patients at 60 months. 5-year freedom from biochemical failure was 95% at our last follow up. Conclusion SIB-IMRT using daily MV-CT guidance showed excellent long-term biochemical control and low toxicity rates.

Purpose: Non–small cell lung cancer (NSCLC) is a fatal disease with poor prognosis. A membrane-bound form of Hsp70 (mHsp70) which is selectively expressed on high-risk tumors serves as a target for mHsp70-targeting natural killer (NK) cells. Patients with advanced mHsp70-positive NSCLC may therefore benefit from a therapeutic intervention involving mHsp70-targeting NK cells. The randomized phase II clinical trial (EudraCT2008-002130-30) explores tolerability and efficacy of ex vivo–activated NK cells in patients with NSCLC after radiochemotherapy (RCT). Patients and Methods: Patients with unresectable, mHsp70-positive NSCLC (stage IIIa/b) received 4 cycles of autologous NK cells activated ex vivo with TKD/IL2 [interventional arm (INT)] after RCT (60–70 Gy, platinum-based chemotherapy) or RCT alone [control arm (CTRL)]. The primary objective was progression-free survival (PFS), and secondary objectives were the assessment of quality of life (QoL, QLQ-LC13), toxicity, and immunobiological responses. Results: The NK-cell therapy after RCT was well tolerated, and no differences in QoL parameters between the two study arms were detected. Estimated 1-year probabilities for PFS were 67% [95% confidence interval (CI), 19%–90%] for the INT arm and 33% (95% CI, 5%–68%) for the CTRL arm (P = 0.36, 1-sided log-rank test). Clinical responses in the INT group were associated with an increase in the prevalence of activated NK cells in their peripheral blood. Conclusions: Ex vivo TKD/IL2-activated, autologous NK cells are well tolerated and deliver positive clinical responses in patients with advanced NSCLC after RCT.

The aim of the study was to assess the importance of surrounding tissues for the delineation of moving targets in tissue-specific phantoms and to find optimal settings for lung, soft tissue, and liver tumors.Tumor movement was simulated by a water-filled table tennis ball (target volume, TV). Three phantoms were created: corkboards to simulate lung tissue (lung phantom, LunPh), animal fat as fatty soft tissue (fatty tissue phantom, FatPh), and water enhanced with contrast medium as the liver tissue (liver phantom, LivPh). Slow planning three-dimensional compute tomography images (3D-CTs) were acquired with and without phantom movements. One-dimensional tumor movement (1D), three-dimensional tumor movement (3D), as well as a real patient's tumor trajectories were simulated. The TV was contoured using two lung window settings, two soft-tissue window settings, and one liver window setting. The volumes were compared to mathematical calculated values.TVs were underestimated in all phantoms due to movement. The use of soft-tissue windows in the LivPh led to a significant underestimation of the TV (70.8% of calculated TV). When common window settings [LunPh + 200 HU/-1,000 HU (upper window/lower window threshold); FatPh: + 240 HU/-120 HU; LivPh: + 175 HU/+ 50 HU] were used, the contoured TVs were: LivPh, 84.0%; LunPh, 93.2%, and FatPh, 92.8%. The lower window threshold had a significant impact on the size of the delineated TV, whereas changes of the upper threshold led only to small differences.The decisive factor for window settings is the lower window threshold (for adequate TV delineation in the lung and fatty-soft tissue it should be lower than density values of surrounding tissue). The use of a liver window should be considered.

Purpose To evaluate long-term clinical outcome and determine prognostic factors for local-control, hearing preservation and cranial nerve toxicity in 449 patients treated for 451 vestibular schwannomas (VS) with radiosurgery ( n =169; 38%) or fractionated stereotactic radiotherapy (FSRT; n =291; 62%). Methods and materials 245 patients were male (55%), and 204 were female (45%). Median age was 60years (range 17–88years). Median tumor diameter was 15mm. For FSRT, a median dose of 57.6Gy in median single doses of 1.8Gy was applied. For SRS, median dose was 13Gy. The median follow-up time was 67months. Results Local control was 97% at 36months, 95% at 60months, and 94% at 120months with no difference between FSRT and SRS ( p =0.39). " Useful hearing " was present 46%. After RT, " useful hearing " was preserved in 85% of the patients. Loss of useful hearing was observed in the FSRT group in 14%, and in the SRS group in 16% of the patients. For patients treated with SRS ⩽13Gy, useful hearing deterioration was 13%. For trigeminal and facial nerve toxicity, there was no difference between FSRT and SRS. Conclusion Supported by this large multicentric series, both SRS and FSRT can be recommended for the treatment of VS. SRS application is limited by tumor size, and is associated with a steep dose–response-curve. When chosen diligently based on tumor volume, pre-treatment characteristics and volume-dependent dose-prescription in SRS (⩽13Gy), both treatments may be considered equally effective.

The aim of this study was to develop a methodology for the comparison of pathology specimens after prostatectomy (post-S) with PET images obtained before surgery (pre-S). This method was used to evaluate the merit of (11)C-choline PET/CT for delineation of gross tumour volume (GTV) in prostate cancer (PC).In 28 PC patients, (11)C-choline PET/CT was performed before surgery. PET/CT data were coregistered with the pathology specimens. GTV on PET images (GTV-PET) was outlined automatically and corrected manually. Tumour volume in the prostate (TVP) was delineated manually on the pathology specimens. Based on the coregistered PET/pathology images, the following parameters were assessed: SUVmax and SUVmean in the tumoral and nontumoral prostate (NP), GTV-PET (millilitres) and TVP (millilitres).PET/pathology image coregistration was satisfactory. Mean SUVmax in the TVP was lower than in the NP: 5.0 and 5.5, respectively (p = 0.093). Considering the entire prostate, SUVmax was located in the TVP in two patients, in the TVP and NP in 12 patients and exclusively in NP in 14 patients. Partial overlap the TVP and GTV-PET was seen in 71% of patients, and complete overlap in 4%.PET/pathology image coregistration can be used for evaluation of different imaging modalities. (11)C-Choline PET failed to distinguish tumour from nontumour tissue.

The purpose of this work is to analyze patterns of care and outcome after stereotactic body radiotherapy (SBRT) for centrally located, early-stage, non-small cell lung cancer (NSCLC) and to address the question of potential risk for increased toxicity in this entity.A total of 90 patients with centrally located NSCLC were identified among 613 cases in a database of 13 German and Austrian academic radiotherapy centers. The outcome of centrally located NSCLC was compared to that of cases with peripheral tumor location from the same database.Patients with central tumors most commonly presented with UICC stage IB (50 %), while the majority of peripheral lesions were stage IA (56 %). Average tumor diameters were 3.3 cm (central) and 2.8 cm (peripheral). Staging PET/CT was available for 73 and 74 % of peripheral and central tumors, respectively. Biopsy was performed in 84 % (peripheral) and 88 % (central) of cases. Doses varied significantly between central and peripheral lesions with a median BED10 of 72 Gy and 84 Gy, respectively (p 0.001). Fractionation differed as well with medians of 5 (central) and 3 (peripheral) fractions (p 0.001). In the Kaplan-Meier analysis, 3-year actuarial overall survival was 29 % (central) and 51 % (peripheral; p = 0.004) and freedom from local progression was 52 % (central) and 84 % (peripheral; p 0.001). Toxicity after treatment of central tumors was low with no grade III/IV and one grade V event. Mortality rates were 0 and 1 % after 30 and 60 days, respectively.Local tumor control in patients treated with SBRT for centrally located, early-stage NSCLC was favorable, provided ablative radiation doses were prescribed. This was, however, not the case in the majority of patients, possibly due to concerns about treatment-related toxicity. Reported toxicity was low, but prospective trials are needed to resolve the existing uncertainties and to establish safe high-dose regimens for this cohort of patients.

The impact of CT window settings on the contouring of a moving target: A phantom study K.J. Borm , M. Oechsner , J.J. Wilkens , J. Berndt , M. Molls , H. Geinitz , M.N. Duma b,* Medical School, Technische Universit€ at M€ unchen, Germany Department of Radiation Oncology, Technische Universit€ at M€ unchen, Klinikum rechts der Isar, Germany Department of Radiation Oncology, Krankenhaus Barmherzige Schwestern Linz, Austria

The purpose of this article is to report the outcome of neoadjuvant radiochemotherapy (N-RCT) + surgery in patients with squamous cell carcinoma of the esophagus at a single institution. We retrospectively reviewed data from patients who were referred to our department for N-RCT. From 1988-2011, 103 patients were treated with N-RCT with cisplatin and/or 5-fluorouracil (5-FU). Group 1: (n = 55) from 1988-2006 with 39.6-40 Gy and 5-FU with (n = 17) or without cisplatin (n = 38). Group 2: from 2003-2010 with 44-45 Gy and 5-FU with (n = 40) or without cisplatin (n = 8). All patients underwent radical resection with reconstruction according to tumor location and 2-field lymph node dissection. The degree of histomorphologic regression was defined as grade 1a (pCR, 0 % residual tumor), grade 1b (pSTR, 50 % residual tumor). Median follow-up time from the start of N-RCT was 100 months (range 2-213 months). The median overall survival (OS) for the whole cohort was 42 months and the 5-year OS was 45 ± 5 %. In the multivariate analysis, worse ECOG performance status (p 10 % before the start of the N- RCT (p = 0.025), higher pT category (p = 0.001), and grade 2/3 pathologic remission (p

To compare the outcomes of two neoadjuvant radiochemotherapy (N-RCT) regimens for squamous cell carcinoma of the esophagus (ESCC).The standard N-RCT regimen for ESCC at our institution between 2002 and 2011 was a total dose of 45 Gy (1.8-Gy fractions) with concomitant cisplatin (20 mg/m(2), days 1-5 and 29-33) and 5-fluorouracil (5-FU; 225 mg/m(2), 24 h continuous infusion on days 1-33). During the same period, a phase I/II study comparing the standard ESCC N-RCT protocol with a regimen identical except for the replacement of cisplatin with weekly oxaliplatin (40-50 mg/m(2)) was performed at our center. The standard regimen was used to treat 40 patients; 37 received the oxaliplatin regimen. All patients subsequently underwent radical resection with reconstruction according to tumor location and two-field lymph node dissection.Median follow-up time from the start of N-RCT was 74 months (range 3-116 months). The two patient groups were comparable in terms of demographic and baseline tumor characteristics. R0 resection was achieved in 37/39 patients (95 %) in the cisplatin-based N-RCT group, compared to 24/37 (65 %) in the oxaliplatin-based group (p = 0.002). A pathological complete response (pCR) was seen in the resection specimens from 18/39 patients (46 %) in the cisplatin-based N-RCT group and in 8/37 (22 %) oxaliplatin-group patients. In the cisplatin group, 2- and 5-year overall survival (OS) rates were 67 ± 8 % and 60 ± 8 %, respectively (median OS 103 months), compared to 38 ± 8 % and 32 ± 8 %, respectively, for the oxaliplatin group (median OS 17 months; hazard ratio, HR 0.452; 95 % confidence interval, CI 0.244-0.839; p = 0.012).Oxaliplatin-based N-RCT resulted in poorer outcomes in ESCC patients and should not routinely replace cisplatin-based N-RCT.

The goal of this work was to investigate the potential of advanced radiation techniques in dose escalation in the radiotherapy (RT) for the treatment of esophageal carcinoma.A total of 15 locally advanced esophageal cancer (LAEC) patients were selected for the present study. For all 15 patients, we created a 3D conformal RT plan (3D-45) with 45 Gy in fractions of 1.8 Gy to the planning target volume (PTV1), which we usually use to employ in the neoadjuvant treatment of LAEC. Additionally, a 3D boost (as in the primary RT of LAEC) was calculated with 9 Gy in fractions of 1.8 Gy to the boost volume (PTV2) (Dmean) to a total dose of 54 Gy (3D-54 Gy), which we routinely use for the definitive treatment of LAEC. Three plans with a simultaneous integrated boost (SIB) were then calculated for each patient: sliding window intensity-modulated radiotherapy (IMRT-SIB), volumetric modulated arc therapy (VMAT-SIB), and helical tomotherapy (HT-SIB). For the SIB plans, the requirement was that 95 % of the PTV1 receive ≥ 100 % of the prescription dose (45 Gy in fractions of 1.8 Gy, D95) and the PTV2 was dose escalated to 52.5 Gy in fractions of 2.1 Gy (D95).The median PTV2 dose for 3D-45, 3D-54, HT-SIB, VMAT-SIB, and IMRT-SIB was 45, 55, 54, 56, and 55 Gy, respectively. Therefore, the dose to PTV2 in the SIB plans was comparable to the 3D-54 plan. The lung dose in the SIB plans was in the range of the standard 3D-45, which is applied for neoadjuvant radiotherapy. The mean lung dose for the same plans was 13, 15, 12, 12, and 13 Gy, respectively. The V5 lung volumes were 71, 74, 79, 75, and 73 %, respectively. The V20 lung volumes were 20, 25, 16, 18, and 19 %, respectively.New treatment planning techniques enable higher doses to be delivered for neoadjuvant radiotherapy of LAEC without a significant increase in the delivered dose to the organs at risk. Clinical investigations are warranted to study the clinical safety and feasibility of applying higher doses through advanced techniques in the neoadjuvant treatment of LAEC.

Purpose Previous studies have shown that the plasminogen activator inhibitor type-1 (PAI-1) and vascular endothelial growth factor (VEGF) are regulated by hypoxia and irradiation and are involved in neoangiogenesis. The aim of this study was to determine in vivo whether changes in PAI-1 and VEGF during fractionated irradiation could predict for radiation resistance. Methods and Materials Six xenografted tumor lines from human squamous cell carcinomas (HSCC) of the head and neck were irradiated with 0, 3, 5, 10, and 15 daily fractions of 2 Gy. The PAI-1 and VEGF antigen levels in tumor lysates were determined by enzyme-linked immunosorbent assay kits. The amounts of PAI-1 and VEGF were compared with the dose to cure 50% of tumors (TCD 50 ). Colocalization of PAI-1, pimonidazole (hypoxia), CD31 (endothelium), and Hoechst 33342 (perfusion) was examined by immunofluorescence. Results Human PAI-1 and VEGF (hVEGF) expression levels were induced by fractionated irradiation in UT-SCC-15, UT-SCC-14, and UT-SCC-5 tumors, and mouse VEGF (msVEGF) was induced only in UT-SCC-5 tumors. High hVEGF levels were significantly associated with radiation sensitivity after 5 fractions ( P =.021), and high msVEGF levels were significantly associated with radiation resistance after 10 fractions ( P =.007). PAI-1 staining was observed in the extracellular matrix, the cytoplasm of fibroblast-like stroma cells, and individual tumor cells at all doses of irradiation. Colocalization studies showed PAI-1 staining close to microvessels. Conclusions These results indicate that the concentration of tumor-specific and host-specific VEGF during fractionated irradiation could provide considerably divergent information for the outcome of radiation therapy.

Purpose To quantify the actual delivered dose to the cervical spinal cord with different image-guided radiotherapy (IGRT) approaches during head and neck (HN) cancer helical tomotherapy. Methods and Materials Twenty HN patients (HNpts) treated with bilateral nodal irradiation were analyzed. Daily megavoltage computed tomography MVCT) scans were performed for setup purposes. The maximum dose on the planning CT scan (plan-Dmax) and the magnitude and localization of the actual delivered Dmax (a-Dmax) were analyzed for four scenarios: daily image-guided radiotherapy (dIGRT), twice weekly IGRT (2×WkIGRT), once weekly IGRT (1×WkIGRT), and no IGRT at all (non-IGRT). The spinal cord was recontoured on 236 MVCTs for each scenario (total, 944 fractions), and the delivered dose was recalculated for each fraction (fx) separately. Results Fifty-one percent of the analyzed fx for dIGRT, 56% of the analyzed fx for the 2×WkIGRT, 62% of the analyzed fx for the 1×WkIGRT, and 63% of the analyzed fx for the non-IGRT scenarios received a higher a-Dmax than the plan-Dmax. The median increase of dose in these fx was 3.3% more for dIGRT, 5.8% more for 2×WkIGRT, 10.0% more for 1×WkIGRT, and 9.5% more for non-IGRT than the plan-Dmax. The median spinal cord volumes receiving a higher dose than the plan-Dmax were 0.02 cm 3 for dIGRT, 0.11 cm 3 for 2×WkIGRT, 0.31 cm 3 for 1×WkIGRT, and 0.22 cm 3 for non-IGRT. Differences between the dIGRT and all other scenarios were statistically significant ( p 0.05). Conclusions Compared to the Dmax of the initial plan, daily IGRT had the smallest increase in dose. Furthermore, daily IGRT had the lowest proportion of fractions and the smallest volumes affected by a dose that was higher than the planned dose. For patients treated with doses close to the tolerance dose of the spinal cord, we recommend daily IGRT. For all other cases, twice weekly IGRT is sufficient.

The use of 4D-[(18)F]fluorodeoxyglucose (FDG) PET/CT in combination with respiratory gated magnet resonance imaging (MRI) in target volume definition for stereotactic radiation of liver metastases was investigated.A total of 18 patients received respiration gated FDG-PET/CT and MRI. Data were fused using a rigid co-registration algorithm. The quality of the co-registration was rated on a scale from 1 (excellent) to 5 (poor) for co-registration of MRI with gated PET and ungated PET. Gross tumor volume (GTV) was delineated in CT (GTV (CT)), MRI (GTV(MRI)), and PET (GTV(PET)). MRI- and PET-based GTVs were defined by three observers each. Interobserver variability was calculated for all patients as well as for subgroups with and without previous treatment of liver metastases. All GTVs were compared for all patients and separately for patients with previous local therapy. In addition, a semiautomatic segmentation algorithm was applied on the PET images.Co-registration between MR and PET images was rated with 3.3 in average when non-gated PET was used and improved significantly (p 0.01) to 2.1 using gated PET. The average GTV(CT) was 51.5 ml, GTV(MRI) 51.8 ml, and the average GTV(PET) 48.1 ml. Volumes delineated in MRI were 9.9% larger compared to those delineated in CT. Volumes delineated in PET were 13.8% larger than in MRI. The differences between the GTVs were more pronounced in patients with previous treatment. The GTVs defined in MRI showed an interobserver variability of 47.9% (84.1% with previous treatment and 26.2% without previous treatment). The PET-defined GTVs showed an interobserver variability of 21% regardless of previous treatment. Semiautomatic segmentation did not provide satisfying results.FDG-PET can distinguish vital tumor tissue and scar tissue, and therefore alters the GTV especially in patients with previous local treatment. In addition, it reduces the interobserver variability significantly compared to MRI. However, respiratory gated PET is necessary for good co-registration of PET and MRI.

The goal of this work was to assess the feasibility of moderately hypofractionated simultaneous integrated-boost intensity-modulated radiotherapy (SIB-IMRT) with helical tomotherapy in patients with localized prostate cancer regarding acute side effects and dose–volume histogram data (DVH data). Acute side effects and DVH data were evaluated of the first 40 intermediate risk prostate cancer patients treated with a definitive daily image-guided SIB-IMRT protocol via helical tomotherapy in our department. The planning target volume including the prostate and the base of the seminal vesicles with safety margins was treated with 70 Gy in 35 fractions. The boost volume containing the prostate and 3 mm safety margins (5 mm craniocaudal) was treated as SIB to a total dose of 76 Gy (2.17 Gy per fraction). Planning constraints for the anterior rectal wall were set in order not to exceed the dose of 76 Gy prescribed to the boost volume. Acute toxicity was evaluated prospectively using a modified CTCAE (Common Terminology Criteria for Adverse Events) score. SIB-IMRT allowed good rectal sparing, although the full boost dose was permitted to the anterior rectal wall. Median rectum dose was 38 Gy in all patients and the median volumes receiving at least 65 Gy (V65), 70 Gy (V70), and 75 Gy (V75) were 13.5%, 9%, and 3%, respectively. No grade 4 toxicity was observed. Acute grade 3 toxicity was observed in 20% of patients involving nocturia only. Grade 2 acute intestinal and urological side effects occurred in 25% and 57.5%, respectively. No correlation was found between acute toxicity and the DVH data. This institutional SIB-IMRT protocol using daily image guidance as a precondition for smaller safety margins allows dose escalation to the prostate without increasing acute toxicity.

The goal of this work was to analyze the response rate and outcome of patients with stage I–III follicular lymphoma (FL) treated with radiotherapy (RT) alone. The records of 50 consecutive patients with stage I–III FL treated with RT alone at our department from 1988–2009 were analyzed. The median age was 60 years (range 32–80 years) with a median follow-up duration of 8 years (range 4–11 years). Clinical staging was performed according to the Ann Arbor system. Stage I: 30 patients (60%), stage II: 15 patients (30%), stage III: 5 patients (10%). Thirty-two patients (64%) presented with nodal disease, 14 patients (28%) presented with disease in extranodal sites, and 4 patients (8%) had nodal and extranodal involvement. The RT field encompassed only the involved Ann Arbor nodal regions (involved-field RT) in 26 patients (52%), mantle and whole abdominopelvic fields in 6 patients (12%), mantle field in 10 patients (20%), whole abdominopelvic fields in 5 patients (10%), and a so-called mini-mantle in 3 patients (6%). The total RT dose ranged from 26–56 Gy (median 40 Gy) in daily fractions of 1.2–2.5 Gy. Complete remission (CR) and partial remission (PR) were observed in 39 (76%) and 9 (20%) patients, respectively. Only 2 of 8 patients (25%) with tumor bulk > 5 cm reached CR, whereas 37 of 42 patients (88%) with a maximum lymphoma diameter

The goal was to retrospectively review the outcome of patients with cervical lymph node metastases of squamuos cell carcinoma of unknown primary site (CUP) treated with radio(chemo)therapy. A total of 65 patients with CUP N1–3, M0, treated between 1988 and 2009 were evaluated: 61 patients underwent surgical resection followed by postoperative radio(chemo)therapy, 4 patients received definitive radiochemotherapy. Radiotherapy of bilateral neck nodes + the parapharyngeal region (COMP-RT) was performed in 48 patients (80%) and a unilateral radiotherapy of lymph nodes (UL-RT) in 17 patients (20%). After a median follow-up time of 64 months (range 3–219 months), the estimated 2- and 5-year overall survival (OS) rates were 71 ± 6% and 48 ± 7%, respectively. The recurrent free survival (RFS) rate at 2- and 5-years was 58 ± 6% and 48% ± 7%, respectively. Extracapsular spread, resection status (R0 vs. R1/R2), neck lymph node level (I–III vs. IV–V), and Karnofsky index (60–70 vs. 80–100) were significant prognostic factors for OS and RFS in the univariate analysis. Lower nodal stage (N1/N2a vs. N2b/N2c/N3) was significantly associated with a better OS. Resection status and involvement of lymph node level IV significantly affected the OS and RFS in the multivariate analysis. COMP-RT or concurrent chemotherapy was not associated with a better OS or RFS. An advantage of comprehensive radiotherapy or radiochemotherapy compared with unilateral radiotherapy of lymph nodes was not observed.

Background and purpose To report patterns of failure of stereotactic body radiation therapy (SBRT) in inoperable patients with histologically confirmed stage I NSCLC. Materials and methods Ninety-two inoperable patients (median age: 75years) with clinically staged, histologically proven T1 ( n =31) or T2 ( n =61), N0, M0 non-small cell lung cancer (NSCLC) were included in this study. Treatment consisted of 3–5 fractions with 7–15Gy per fraction prescribed to the 60% isodose. Results Freedom from local recurrence at 1, 3 and 5years was 89%, 83% and 83%, respectively. All 10 local failures were observed in patients with T2 tumors. Isolated regional recurrence was observed in 7.6%. The crude rate of distant progression was 20.7%. Overall survival at 1, 3, and 5years was 79%, 38% and 17% with a median survival of 29months. Disease specific survival at 1, 3, and 5years was 93%, 64% and 48%. Karnofsky performance status, T stage, gross tumor volume and tumor location had no significant impact on overall and disease specific survival. SBRT was generally well tolerated and all patients completed therapy as planned. Conclusion SBRT for stage I lung cancer is very well tolerated in this patient cohort with significant cardiopulmonal comorbidity and results in excellent local control rates, although a considerable portion develops regional and distant metastases.

SUMMARY The purpose of this study was to report the outcome of radio(chemo)therapy in the curative management of esophageal squamous cell carcinoma (ESCC). We retrospectively analyzed 163 patients with T1-T4, N0-1, M0 ESCC who were treated between January 1988 and December 2006 at the Technische Universitat Munchen. One hundred sixty patients were inoperable due to a poor performance status, comorbidities or locally advanced unresectable disease. External beam radiation therapy (EBRT) was performed with (n= 146) or without (n= 17) systemic chemotherapy. Fifty-four patients received an additional boost with intraluminal brachytherapy (IBT). Surviving patients were followed for a median of 72 months (range 10–173 months). The estimated overall survival (OS) at 2 and 5 years was 27 ± 4% and 11 ± 3%, respectively. Loco-regional recurrence at the primary site was observed in 29% of patients (n= 47). The recurrence-free survival (RFS) at 2 and 5 years was 24 ± 3% and 9 ± 2%, respectively. In multivariate analyses, the ECOG performance status (P= 0.004), 3D conformal (vs conventional) radiotherapy (P= 0.031) and continuous standard fractionation (vs split-course radiotherapy, P= 0.048) were associated with a better OS. Simultaneous chemotherapy (P= 0.49) or IBT (P= 0.31) had no significant impact on survival. Outcome for patients with ESCC is poor. Despite the very unfavorable patient selection (poor performance status, high rate of comorbidities, and advanced disease), long-term survival with radio(chemo)therapy was achieved in about 10% of patients. The introduction of modern treatment techniques/modalities (3D conformal planning/ continuous standard fractionation) might be associated with better outcomes.

Purpose Several retrospective analyses have suggested that obese men with prostate cancer treated with external beam radiotherapy (EBRT) have outcomes inferior to those of normal-weight men. However, a recently presented analysis for the first time challenged this association between body mass index (BMI) and treatment failure. It is therefore important to provide further data on this issue. Methods and Materials This was a retrospective analysis of 564 men treated with risk-adapted conformal EBRT at a single institution. Low-risk patients received EBRT alone, and the other patients received EBRT plus endocrine treatment. In addition, high-risk patients were treated to higher EBRT doses (74 Gy). A rectal balloon catheter for internal immobilization, which can be identified on portal images, was used in 261 patients (46%). Thus, localization did not rely on bony landmarks alone in these cases. Results The median BMI was 26, and 15% of patients had BMI ≥30. Neither univariate nor multivariate analyses detected any significant impact of BMI on biochemical relapse, prostate cancer–specific survival, or overall survival. The 5-year biochemical relapse rate was 21% and prostate cancerspecific survival 96%. Conclusions The present analysis of a large cohort of consecutively treated patients suggests that efforts to reduce prostate movement and geographic miss might result in comparable outcomes in obese and normal-weight patients.

Background and purpose The major stress-inducible heat shock protein 70 (Hsp70) is frequently overexpressed in highly aggressive tumors, and elevated intracellular Hsp70 levels mediate protection against apoptosis. Following therapeutic intervention, such as ionizing irradiation, translocation of cytosolic Hsp70 to the plasma membrane is selectively increased in tumor cells and therefore, membrane Hsp70 might serve as a therapy-inducible, tumor-specific target structure. Materials and methods Based on the IgG1 mouse monoclonal antibody (mAb) cmHsp70.1, we produced the Hsp70-specific recombinant Fab fragment (Hsp70 Fab), as an imaging tool for the detection of membrane Hsp70 positive tumor cells in vitro and in vivo . Results The binding characteristics of Hsp70 Fab towards mouse colon (CT26) and pancreatic (1048) carcinoma cells at 4°C were comparable to that of cmHsp70.1 mAb, as determined by flow cytometry. Following a temperature shift to 37°C, Hsp70 Fab rapidly translocates into subcellular vesicles of mouse tumor cells. Furthermore, in tumor-bearing mice Cy5.5-conjugated Hsp70 Fab, but not unrelated IN-1 control Fab fragment (IN-1 ctrl Fab), gradually accumulates in CT26 tumors between 12 and 55h after i.v. injection. Conclusions In summary, the Hsp70 Fab provides an innovative, low immunogenic tool for imaging of membrane Hsp70 positive tumors, in vivo .

A technical set-up for irradiation of subcutaneous tumours in mice with nanosecond-pulsed proton beams or continuous proton beams is described and was successfully used in a first experiment to explore future potential of laser-driven particle beams, which are pulsed due to the acceleration process, for radiation therapy. The chosen concept uses a microbeam approach. By focusing the beam to approximately 100 × 100 μm(2), the necessary fluence of 10(9) protons per cm(2) to deliver a dose of 20 Gy with one-nanosecond shot in the Bragg peak of 23 MeV protons is achieved. Electrical and mechanical beam scanning combines rapid dose delivery with large scan ranges. Aluminium sheets one millimetre in front of the target are used as beam energy degrader, necessary for adjusting the depth-dose profile. The required procedures for treatment planning and dose verification are presented. In a first experiment, 24 tumours in mice were successfully irradiated with 23 MeV protons and a single dose of 20 Gy in pulsed or continuous mode with dose differences between both modes of 10%. So far, no significant difference in tumour growth delay was observed.

Purpose To prospectively assess the intestinal symptoms and fecal continence in patients who had undergone conformal radiotherapy (CRT) for prostate cancer. Methods and Materials A total of 78 men who had undergone definitive CRT for prostate cancer were evaluated. The patients were assessed before, during (treatment Weeks 4 and 6), and 2, 12, and 24 months after CRT completion. The intestinal symptoms and fecal continence were evaluated with comprehensive standardized questionnaires. Results The intestinal symptoms were mostly intermittent, with only a small minority of patients affected daily. Defecation pain, fecal urge, and rectal mucous discharge increased significantly during therapy. Defecation pain and rectal mucous discharge had returned to baseline levels within 8 weeks and 1 year after CRT, respectively. However, fecal urge remained significantly elevated for ≤1 year and then returned toward the pretreatment values. The prevalence of rectal bleeding was significantly elevated 2 years after CRT. Fecal continence deteriorated during CRT and remained impaired at 1 year after treatment. Incontinence was mostly minor, occurring less than once per week and predominantly affecting incontinence for gas. Conclusion Intestinal symptoms and fecal incontinence increased during prostate CRT. Except for rectal bleeding, the intestinal symptoms, including fecal incontinence, returned to baseline levels within 1–2 years after CRT. Thus, the rate of long-term late radiation-related intestinal toxicity was low.

Die steigende Lebenserwartung stellt die Frage nach der besten Behandlungsform fur altere Brustkrebspatientinnen im Fruhstadium nach brusterhaltender Operation. Im generellen Therapiekonzept des Brusterhalts nehmen die adjuvante Strahlentherapie seit uber 20 Jahren und die antihormonelle Therapie einen festen Platz ein. Die Veroffentlichung der Studie von Hughes et al. auf dem ASCO-Kongress 2010 stellt die Notwendigkeit der etablierten adjuvanten Strahlentherapie bei der alteren Patientin infrage. Durch Vergleich verschiedener Untersuchungen soll versucht werden, Losungsansatze fur die Indikationsstellung zur adjuvanten Strahlentherapie zu ermoglichen. Dabei muss beachtet werden, dass es eine allgemein gultige Methode auch hier nicht gibt.

Purpose To evaluate the effect of trimodal image fusion using computed tomography (CT), magnetic resonance imaging (MRI) and 11 C-methionine positron emission tomography (MET-PET) for gross tumor volume delineation in fractionated stereotactic radiotherapy of skull base meningiomas. Patients and Methods In 32 patients with skull base meningiomas, the gross tumor volume (GTV) was outlined on CT scans fused to contrast-enhanced MRI (GTV-MRI/CT). A second GTV, encompassing the MET-PET positive region only (GTV-PET), was generated. The additional information obtained by MET-PET concerning the GTV delineation was evaluated using the PET/CT/MRI co-registered images. The sizes of the overlapping regions of GTV-MRI/CT and GTV-PET were calculated and the amounts of additional volumes added by the complementing modality determined. Results The addition of MET-PET was beneficial for GTV delineation in all but 3 patients. MET-PET detected small tumor portions with a mean volume of 1.6 ± 1.7 cm 3 that were not identified by CT or MRI. The mean percentage of enlargement of the GTV using MET-PET as an additional imaging method was 9.4% ± 10.7%. Conclusions Our data have demonstrated that integration of MET-PET in radiotherapy planning of skull base meningiomas can influence the GTV, possibly resulting in an increase, as well as in a decrease.

Oxaliplatin and 5-fluorouracil have a significant activity in locally advanced oesophageal squamous cell cancer (OSCC). However, their optimal dosage and efficacy when combined with concurrent radiotherapy as neoadjuvant treatment are unknown. This non-randomised, phase I/II study aimed to define the maximum tolerated dose (MTD) and assessed the histopathological tumour response rate to neoadjuvant oxaliplatin in weekly escalating doses (40, 45, 50 mg m(-2)) and continuous infusional 5-fluorouracil (CI-5FU; 225 mg m(-2)) plus concurrent radiotherapy. Patients had resectable OSCC. Resection was scheduled for 4-6 weeks after chemoradiotherapy. During phase I (dose escalation; n=19), weekly oxaliplatin 45 mg m(-2) plus CI-5FU 225 mg m(-2) was established as the MTD and was the recommended dosage for phase II. Oesophageal mucositis was the dose-limiting toxicity at higher doses. During phase II, histopathological responses (10% residual tumour cells within the specimen) were observed in 10 of 16 patients (63%; 95% confidence interval: 39-82%). Overall, 16 of the 25 patients (64%) who underwent resection had a histopathological response; tumour-free resection (R0) was achieved in 80%. Neoadjuvant weekly oxaliplatin 45 mg m(-2) plus CI-5FU 225 mg m(-2) with concurrent radiotherapy provides promising histological response rates and R0 resection rates in locally advanced OSCC.

The purpose of this review is to assess the palliative effect of re-irradiation in adult patients with recurrent supratentorial glioblastoma (GBM) previously treated with adjuvant or primary radiation therapy, with or without chemotherapy. From a comprehensive literature search, studies were identified reporting on survival, progression, and quality of life endpoints including, but not limited to, EORTC QLQ-C30 questionnaire, clinical symptoms, and ability to reduce dexamethasone. Data from more than 300 GBM patients (grade 3 anaplastic gliomas were excluded) demonstrate that re-irradiation yields 6-month PFS of 28% to 39% and 1-year overall survival of 18% to 48%, without additional chemotherapy (median value 26%). Patients with Karnofsky performance status

Summary Objectives: To clarify challenges and research topics for informatics in health and to describe new approaches for interdisciplinary collaboration and education. Methods: Research challenges and possible solutions were elaborated by scientists of two universities using an interdisciplinary approach, in a series of meetings over several months. Results and Conclusion: In order to translate scientific results from bench to bedside and further into an evidence-based and efficient health system, intensive collaboration is needed between experts from medicine, biology, informatics, engineering, public health, as well as social and economic sciences. Research challenges can be attributed to four areas: bioinformatics and systems biology, biomedical engineering and informatics, health informatics and individual healthcare, and public health informatics. In order to bridge existing gaps between different disciplines and cultures, we suggest focusing on interdisciplinary education, taking an integrative approach and starting interdisciplinary practice at early stages of education.* See more detailed authors´ affiliations at the end of the article.

BACKGROUND: Recent studies showed improved local control after preoperative radiochemotherapy (RCTX) in patients with locally advanced rectal carcinoma, but failed to demonstrate a survival benefit. Our aims were to determine outcome and impact of histopathological response after preoperative RCTX. METHODS: One hundred four patients with uT3 rectal carcinoma were treated with preoperative RCTX of 45 Gy and continuous 5-FU infusion between 1997 and 2001 (group I). Histopathological response was evaluated in all specimens after tumor resection. Group II consisted of 114 patients with uT3 rectal carcinoma treated with postoperative RCTX between 1988 and 1997. RESULTS: Group I showed a 6.1% 5-year local recurrence rate compared to 15.3% in group II (P = 0.023). Overall survival rates did not differ significantly between both groups (P = 0.225). Histopathological responders had a significantly improved 5-year overall survival with 89.1 (7.8)% compared to 68.7 (6.7)% of the non-responders (P = 0.008) and were identified as an independent prognostic factor. CONCLUSIONS: Significant improvement of overall survival was observed for histopathological tumor responders after neoadjuvant radiochemotherapy. Our protocol of preoperative radiochemotherapy confirms the results of the multi-center studies in regard to local control and overall survival.

Purpose To evaluate the role of hypoxia positron emission tomography (PET) using [ 18 F]fluoroazomycin-arabinoside (FAZA) in head and neck cancer for radiation treatment planning using intensity-modulated radiotherapy and dose painting. Methods and Materials Eighteen patients with advanced squamous cell head and neck cancer were included. Both FAZA-PET and axial CT were performed using mask fixation. The data were coregistered using software based on mutual information. Contours of tumor (primary gross tumor volume, GTV/CT-P) and lymph node metastases (GTV/CT-N) were outlined manually, and FAZA standardized uptake values (SUVs) were calculated automatically. The hypoxic subvolume (GTV/PET-FAZA) having at least 50% more FAZA uptake than background (mean SUV) neck muscle tissue was contoured automatically within GTV/CT-P (GTV/PET-FAZA-P) and GTV/CT-N (GTV/PET-FAZA-N). Results The median GTV/PET-FAZA-P was 4.6 mL, representing 10.8% (range, 0.7–52%) of the GTV/CT-P. The GTV/PET-FAZA-P failed to correlate significantly with the GTV/CT-P ( p = 0.06). The median GTV/PET-FAZA-N was 4.1 mL, representing 8.3% (range, 2.2–51.3%) of the GTV/CT-N. It was significantly correlated with the GTV/PET-N ( p = 0.006). The GTV/PET-FAZA-P was located in a single confluent area in 11 of 18 patients (61%) and was diffusely dispersed in the whole GTV/CT-P in 4 of 18 patients (22%), whereas no hypoxic areas were identified in 3 of 18 patients (17%). The GTV/PET-FAZA-N was outlined as a single confluent region in 7 of 18 patients (39%), in multiple diffuse hypoxic regions in 4 of 18 patients (22%), and was not delineated in 7 of 18 patients (39%). Conclusion This study demonstrates that FAZA-PET imaging could be used for a hypoxia-directed intensity-modulated radiotherapy approach in head and neck cancer.

Purpose To evaluate outcome in patients with base of skull meningiomas treated with modern high precision radiation therapy (RT) techniques. Patients and methods 927 patients from three centers were treated with either radiosurgery or fractionated high-precision RT for meningiomas. Treatment planning was based on CT and MRI following institutional guidelines. For radiosurgery, a median dose of 13 Gy was applied, for fractionated treatments, a median dose of 54 Gy in 1.8 Gy single fractions was prescribed. Follow-up included a clinical examination as well as contrast-enhanced imaging. All patients were followed up prospectively after radiotherapy in the three departments within a strict follow-up regimen. The median follow-up time was 81 months (range 1–348 months). Results Median local control was 79 months (range 1–348 months). Local control (LC) was 98% at 1 year, 94% at 3 years, 92% at 5 years and 86% at 10 years. There was no difference between radiosurgery and fractionated RT. We analyzed the influence of higher doses on LC and could show that dose did not impact LC. Moreover, there was no difference between 54 Gy and 57.6 Gy in the fractionated group. Side effects were below 5% in both groups without any severe treatment-related complications. Discussion Based on the pooled data analysis this manuscript provides a large series of meningiomas of the skull base treated with modern high precision RT demonstrating excellent local control and low rates of side effects. Such data support the recommendation of RT for skull base meningiomas in the interdisciplinary tumor board discussions. The strong role of RT must influence treatment recommendations keeping in mind the individual risk–benefit profile of treatment alternatives.

In this retrospective evaluation, we correlated radiation dose parameters with occurrence of optical radiation-induced toxicities. 213 meningioma patients received radiation between 2000 and 2013. Radiation dose and clinical data were extracted from planning systems and patients' files. The range of follow-up period was 2-159 months (median 75 months). Median age of patients was 60 years (range 23-86). There were 163 female and 50 male patients. In 140 cases, at least one of the neuro-optic structures (optic nerves and chiasm) was inside the irradiated target volumes. We found 15 dry eye (7 %) and 24 cataract (11.2 %) cases. Median dose to affected lachrymal glands was 1.47 Gy and median dose to affected lenses was 1.05 Gy. Age and blood cholesterol level in patients with cataract were significantly higher. Patients with dry eye were significantly older. Only two patients with visual problems attributable to radiation treatment were seen. They did not have any risk factors. Maximum and median delivered doses to neuro-optic structures were not higher than 57.30 and 54.60 Gy respectively. Low percentages of cases with radiation induced high grade optic toxicities show that modern treatment techniques and doses are safe. In very few patients with optic side effects, doses to organs at risk were higher than the defined constraint doses. This observation leads to the problem of additional risk factors coming into play. The role of risk factors and safety of higher radiation doses in high grade meningiomas should be investigated in more comprehensive studies.

Purpose To report on outcome and toxicity of stereotactic body radiotherapy (SBRT) for liver metastases in patients not eligible for surgery. Methods From 2000 to 2009, 74 patients with 91 liver metastases from different primaries have been treated with SBRT at our institution. Median planning target volume was 123 ccm (range: 10.6-1074 ccm). Treatment consisted of 3–5 fractions with 5–12.5 Gy/ fraction prescribed to the surrounding 60-95% isodose with daily image guidance. Regular follow-up included CT or MRI imaging until tumor progression. Results Median local recurrence-free interval was 23 months with a local control rate of 74.7%, 48.3% and 48.3% after 1, 2 and 3 years. Only minimum biologically effective dose (BED) to gross tumor volume (GTV) remained as independent significant factor for local control in multivariate analysis. No local recurrences were observed in lesions (n = 12) which received a minimal BED to the GTV of 120 Gy. Including 26 local recurrences, 67 patients (91%) showed disease progression after SBRT with a median time of 5 months. Median overall survival was 27 months with survival rates of 77%, 30% and 27% at 1, 3 and 5 years. On multivariate analysis only GTV volume remained as independent significant prognostic factor for overall survival (p = 0.002). No grade 3 to 5 acute toxicity and no grade 4 or 5 late toxicity occurred. Conclusion SBRT for liver metastases was well tolerated in this non-selected patient cohort and yielded good local control despite the considerable size of most lesions treated. Long-term survival is possible after SBRT. Electronic supplementary material The online version of this article (doi:10.1186/s13014-015-0369-9) contains supplementary material, which is available to authorized users.

BACKGROUND: The major stress-inducible heat shock protein 70 (Hsp70) is frequently overexpressed in the cytosol and integrated in the plasma membrane of tumor cells via lipid anchorage. Following stress such as non-lethal irradiation Hsp70 synthesis is up-regulated. Intracellular located Hsp70 is known to exert cytoprotective properties, however, less is known about membrane (m)Hsp70. Herein, we investigate the role of mHsp70 in the sensitivity towards irradiation in tumor sublines that differ in their cytosolic and/or mHsp70 levels. METHODS: The isogenic human colon carcinoma sublines CX(+) with stable high and CX(-) with stable low expression of mHsp70 were generated by fluorescence activated cell sorting, the mouse mammary carcinoma sublines 4T1 (4T1 ctrl) and Hsp70 knock-down (4T1 Hsp70 KD) were produced using the CRISPR/Cas9 system, and the Hsp70 down-regulation in human lung carcinoma sublines H1339 ctrl/H1339 HSF-1 KD and EPLC-272H ctrl/EPLC-272H HSF-1 KD was achieved by small interfering (si)RNA against Heat shock factor 1 (HSF-1). Cytosolic and mHsp70 was quantified by Western blot analysis/ELISA and flow cytometry; double strand breaks (DSBs) and apoptosis were measured by flow cytometry using antibodies against γH2AX and real-time PCR (RT-PCR) using primers and antibodies directed against apoptosis related genes; and radiation sensitivity was determined using clonogenic cell surviving assays. RESULTS: CX(+)/CX(-) tumor cells exhibited similar cytosolic but differed significantly in their mHsp70 levels, 4T1 ctrl/4T1 Hsp70 KD cells showed significant differences in their cytosolic and mHsp70 levels and H1339 ctrl/H1339 HSF-1 KD and EPLC-272H ctrl/EPLC-272H HSF-1 KD lung carcinoma cell sublines had similar mHsp70 but significantly different cytosolic Hsp70 levels. γH2AX was significantly up-regulated in irradiated CX(-) and 4T1 Hsp70 KD with low basal mHsp70 levels, but not in their mHsp70 high expressing counterparts, irrespectively of their cytosolic Hsp70 content. After irradiation γH2AX, Caspase 3/7 and Annexin V were up-regulated in the lung carcinoma sublines, but no significant differences were observed in H1339 ctrl/H1339 HSF-1 KD, and EPLC-272H ctrl/EPLC-272H HSF-1 KD that exhibit identical mHsp70 but different cytosolic Hsp70 levels. Clonogenic cell survival was significantly lower in CX(-) and 4T1 Hsp70 KD cells with low mHsp70 expression, than in CX+ and 4T1 ctrl cells, whereas no difference in clonogenic cell survival was observed in H1339 ctrl/H1339 HSF-1 KD and EPLC-272H ctrl/ EPLC-272H HSF-1 KD sublines with identical mHsp70 but different cytosolic Hsp70 levels. CONCLUSION: In summary, our results indicate that mHsp70 has an impact on radiation resistance.

Despite of postoperative radiotherapy plus temozolomide for newly diagnosed glioblastoma multiforme (GBM) and improvements in the molecular characterization of high-grade glioma, these tumors continue to relapse. We reviewed all clinical studies of re-treatment published between May 2000 and September 2005. In groups of highly selected patients with re-treatment for GBM, median survival reaches 26-27 months. Re-treatment was stereotactic radiotherapy (mostly with additional chemotherapy) or re-resection plus either photodynamic treatment, radioimmunotherapy and temozolomide, or systemic and local chemotherapy. Thus, intense local treatment was always a component of more successful strategies. Additional data suggest that chemotherapy is more efficacious when minimal residual disease is present, although the recent trials have not uncovered a clear regimen of choice. Early trials of immunotherapy and toxin-delivery demonstrate the feasibility of these approaches and encouraging median survival times. Response to erlotinib was more common if tumors had epidermal growth factor receptor gene amplification, protein overexpression and low levels of phosphorylated PKB/Akt. Individual tailoring of such strategies based on molecular profiling is hoped to improve the outcome.

Angiogenesis inhibitors combined with cytotoxic chemotherapy have recently entered routine oncological practice. Several rationales exist for combining these agents with ionizing radiation, a primary curative cancer treatment, either in bimodal or trimodal fashion, i.e. with or without additional chemotherapy. More than 20 different anti-angiogenic agents have been studied in preclinical animal tumor models. This systematic review compares the results of preclinical studies published before February 2006. The combination of vascular endothelial growth factor (VEGF) inhibitors with irradiation consistently resulted in improved tumor growth delay (at least additive effects), despite different radiation schedules, drugs and doses, and combination regimens. Only two studies evaluated tumor control dose (TCD)50 as a measure of tumor cure (radiation dose yielding permanent local control in 50% of the tumors). While anti-VEGF receptor (VEGFR) antibody treatment improved the outcome, a VEGFR tyrosine kinase inhibitor showed negative results. For agents interfering with other pathways, the results are also not consistent, although most studies were positive. Trimodal approaches seem to improve tumor growth delay even further. Importantly, both radiotherapy schedule and sequence of the modalities in combined treatment may impact on the outcome. Hence, further preclinical studies examining these parameters need to be conducted. While preclinical research is ongoing, phase I and II clinical trials with bevacizumab, combretastatin A-4, thalidomide and different receptor tyrosine kinase inhibitors, usually combined with radio- and chemotherapy, have been designed. Early results suggest that acute toxicity is acceptable, planned surgery after such treatment is feasible, and that further evaluation of such combined modality treatment is warranted.

To describe an emerging concept of high-precision radiotherapy, a modality characterized by adaptation to patient and organ movements, which might occur between fractions or even during radiation delivery. Today’s unprecedented technical capabilities to visualize the target volume and create conformal dose distributions allow for avoidance of critical structures or targeted treatment intensification within a conventionally imaged, anatomically defined tumor. The success of selective dose escalation depends on (1) correct staging and target volume identification, which can be improved by biological imaging, and (2) identification of biologically relevant subvolumes, which determine tumor control. Current efforts are directed at different methods, such as positron emission tomography and magnetic resonance spectroscopy, and integrating them into treatment planning. Early clinical trials assessing the safety and efficacy of image- and biology-guided radiotherapy are ongoing. The same modalities might be used to determine the individual tumor response during treatment and to adapt therapy. Temporal changes in tumor biology, which might represent both a challenge and a chance with regard to adaptation of treatment, need to be addressed in greater detail.

Summary Background Radiation damage to skin is a key diagnostic and prognostic parameter for patients accidentally exposed to radiation. Moreover, skin is a target organ for crucial side-effects of routine radiotherapy. The pathophysiology of the cutaneous radiation reaction is in many respects still unknown. The acute inflammatory radiation reaction of skin has been shown to involve alterations in cell–cell and cell–matrix interactions, which are mediated by cellular adhesion molecules. Objectives To evaluate the effect of ionizing radiation on intercellular adhesion molecule-1 (ICAM-1) expression in human skin cells. Methods Dermal monolayer cells, a three-dimensional skin model and skin biopsies were investigated for ICAM-1 expression after ionizing radiation using flow cytometry, quantitative reverse transcription–polymerase chain reaction and immunohistochemistry. ICAM-1 expression in monolayer cells pretreated with protein kinase inhibitors and dexamethasone prior to irradiation was analysed by flow cytometry. Results Using different sources of skin cells, we demonstrated a consistent upregulation of both ICAM-1 mRNA and protein expression by ionizing radiation. Blocking experiments revealed that tumour necrosis factor-α, another ICAM-1 inducer, does not account for the effect of radiation. Radiation-induced upregulation of ICAM-1 expression was significantly attenuated by inhibitors to protein kinase C, mitogen-activated protein (MAP) ERK kinase, p38 MAP kinase and phosphatidylinositol 3-kinase. The anti-inflammatory agent dexamethasone suppressed the effect of radiation on ICAM-1 expression, suggesting its usefulness to treat the cutaneous radiation reaction. Conclusions Our data suggest that ICAM-1 is a consistent inflammatory parameter of the cutaneous radiation reaction both in vitro and in vivo that might provide new therapeutic options for diagnosis and treatment of effects of radiation.

BACKGROUND AND PURPOSE: Tirapazamine (TPZ) is an anticancer drug that is selectively activated by the low oxygen environment in solid tumors. Furthermore, TPZ also enhances the tumor cell-killing effect of cisplatin. So far, detailed information on the toxicity of combined treatment is rare. The authors evaluated the toxicity of TPZ in combination with cisplatin in a mouse tumor model. For this purpose, general toxicity was monitored and all inner organs were examined histologically. MATERIAL AND METHODS: RIF-1 fibrosarcomas of murine origin growing in the right hindfoot dorsum of C3H mice were used. The animals were treated with 10 x 2 Gy irradiation plus six i.p. injections of 4 mg/kg cisplatin (total dose 24 mg/kg) together with varying doses of TPZ (0-28 mg/kg per injection; total dose 0, 43.2, 86.4, 129.6, 151.2, 172.8 mg/kg). Treatment was applied within 2 weeks (Figure 1). Total observation period was up to 35 days. RESULTS: Combined treatment with TPZ led to a dose-dependent, significant decrease in motor activity (Table 1) and body weight and an increase in mortality (Figures 2 and 3, Tables 2 and 3). Histological analyses showed areas of necrosis in the heart, liver and kidney and gastric ulcers (Table 4). Cisplatin alone produced no severe toxicity. Tumor doubling times were TPZ dose-dependent and comparable with data from the literature (Figures 4 and 5, Table 3). CONCLUSION: Unlike most data from the literature a dose-dependent increase in toxicity was seen when adding TPZ to a standard treatment of cisplatin plus irradiation. To the authors' knowledge this is the first study histologically examining in detail the organ toxicity of TPZ in a mouse model. Furthermore, they expand the rare data on long-term toxicity after TPZ plus cisplatin in a fractionated therapy regimen. The results question the usefulness of frequently performed therapeutic studies where only short-term treatment and observation endpoints are used, since essential toxicities are likely to be overlooked.

Purpose: To examine retrospectively the maximum dose to the large skull base/intracranial arteries in fractionated stereotactic radiotherapy (FSRT) and intensity-modulated radiotherapy (IMRT), because of the potential risk of perfusion disturbances. Methods and Materials: Overall, 56 patients with tumors adjacent to at least one major artery were analyzed. Our strategy was to perform FSRT with these criteria: 1.8 Gy per fraction, planning target volume (PTV) enclosed by the 95% isodose, maximum dose 107%. Dose limits were applied to established organs at risk, but not the vessels. If FSRT planning failed to meet any of these criteria, IMRT was planned with the same objectives. Results: In 31 patients (median PTV, 23 cm 3 ), the FSRT plan fulfilled all criteria. No artery received a dose ≥105%. Twenty-five patients (median PTV, 39 cm 3 ) needed IMRT planning. In 11 of 25 patients (median PTV, 85 cm 3 ), no plan satisfying all our criteria could be calculated. Only in this group, moderately increased maximum vessel doses were observed (106–110%, n = 7, median PTV, 121 cm 3 ). The median PTV dose gradient was 29% (significantly different from the 14 patients with satisfactory IMRT plans). Three of the four patients in this group had paranasal sinus tumors. Conclusion: The doses to the major arteries should be calculated in IMRT planning for critical tumor locations if a dose gradient >13% within the PTV can not be avoided because the PTV is large or includes air cavities.

Stereotactic Radiotherapy has the potential to produce high local control rates with low risk of severe lung toxicity. From December 2000 to January 2006, 68 inoperable patients (median age 76 years) with stage I NSCLC received definitive hSRT. A mean total dose of 37.5 Gy (24-40 Gy; 60%-isodose) in 3-5 fractions was applied. Immobilisation was carried out by means of a vacuum couch and low pressure foil (Medical Intelligence, Schwab München, Germany). Staging procedures were thoracic and abdominal CT-scan, FDG-PET and CT or MRI of the brain in all patients. Clinical target volume was the tumor as seen in lung windowing of CT and in FDG-PET. Organ movements (6-22 mm) and patient positioning in the couch (3-12 mm) were added as safety margin for the definition of the planning target volume (PTV), that was enclosed by the 60%-isodose. We observed four (6%) local tumor recurrences, resulting in an actuarial local tumor control rate of 96%, 88% and 88% after 1, 2 and 3 year follow-up. Nineteen patients died, with eight patients due to cancer (12%), two to local tumor progression alone. Cancer-specific survival is 96%, 82% and 73% at 1, 2 and 3 years. Eleven patients died from comorbidities, making a 53% overall 3-year survival. Fifty five percent of the patients were affected by mild acute and subacute side effects, with only 3% experiencing pneumonitis III degrees . Late effects were pneumonitis III degrees in 1%, rib fractures in 3%, and benign pleural effusion in 2 patients. Hypofractionated SRT is safe even in elderly patients with stage I NSCLC and significantly reduced lung capacity. It leads to high local control rates and should be offered to patients not amenable for curative resection.

BACKGROUND The objectives of this study were to investigate histomorphologic features as a response classification after neoadjuvant radiochemotherapy (RTx/CTx) and to correlate the results with clinical outcome parameters (e.g., postoperative morbidity and mortality, recurrence, and survival) in patients with locally advanced esophageal squamous cell carcinoma (ESCC). METHODS Three hundred eleven patients with histologically proven, locally advanced, intrathoracic ESCC (clinical T3 or T4, N0-N+, M0) located at or above the level of the tracheal bifurcation underwent preoperative, combined, simultaneous RTx/CTx followed by esophagectomy. Response to RTx/CTx was classified by the quantification of residual tumor cells. A histopathologic response was defined as 10% residual tumor cells. RESULTS A histopathologic response was correlated significantly with complete tumor resection status (R0 resection) (P .0001), histopathologic tumor (ypT) category (P

Purpose: Radiation-induced chromosome aberrations are routinely used in biologic dosimetry to monitor radiation exposure. Translocations are considered stable aberrations with time after exposure. This study was performed to determine the temporal persistence of radiation-induced translocations during a 36-month period in therapeutically irradiated testicular seminoma patients who underwent partial body exposure (>10% of bone marrow). Methods and Materials: Chromosome analyses were carried out in peripheral lymphocytes of 11 patients with testicular seminoma ( n = 9), germinoma ( n = 1), or follicular non-Hodgkin's lymphoma ( n = 1). All patients received radiotherapy with photons from a linear accelerator; in 1 case, additional electron beams were used. Doses ranged from 26 Gy (seminoma) to 45 Gy (non-Hodgkin's lymphoma). None of the patients received chemotherapy. From each patient, blood samples were taken during the 36 months after irradiation at defined points. Chromosomal aberrations were scored after fluorescence in situ hybridization painting of chromosomes 1, 4, and 12 in combination with a pancentromeric probe. Results: For 9 patients (7 with testicular seminoma, 1 with germinoma, and 1 with non-Hodgkin's lymphoma), a significant temporal decline of translocations, with a mean decline rate of 4.4% ± 0.4% monthly, could be detected. Two testicular seminoma patients showed no temporal decline of aberration frequencies. Conclusion: Most partial body irradiated patients (9 of 11) showed a significant temporal decline of translocation frequencies during a 36-month period. Thus, reciprocal translocations after partial body irradiation cannot be regarded as stable over time. The temporal decline of aberration frequencies has to be taken into account for retrospective dose estimations.

Purpose: Using magnetic resonance imaging (MRI), residual tumor cannot be differentiated from nonspecific postoperative changes in operated patients with brain gliomas. The higher specificity and sensitivity of l-(methyl-11C)-labeled methionine positron emissions tomography (MET-PET) in gliomas has been demonstrated in previous studies and is the rationale for the integration of this investigation in gross tumor volume delineation. The goal of this trial was to quantify the affect of MET-PET vs. with MRI in gross tumor volume definition for radiotherapy planning of high-grade gliomas. Methods and Materials: The trial included 39 patients with resected malignant gliomas. MRI and MET-PET data were coregistered based on mutual information. The residual tumor volume on MET-PET and the volume of tissue abnormalities on T 1 -weighted MRI (gadolinium [Gd] enhancement) and T 2 -weighted MRI (hyperintensity areas) were compared using MET-PET/MRI fusion images. Results: The MET-PET vs. Gd-enhanced T 1 -weighted MRI analysis was performed on 39 patients. In 5 patients (13%), MET uptake corresponded exactly with Gd enhancement, and in 29 (74%) of 39 patients, the region of MET uptake was larger than that of the Gd enhancement. In 27 (69%) of the 39 patients, the Gd enhancement area extended beyond the MET enhancement. MET uptake was detected up to 45 mm beyond the Gd enhancement. MET-PET vs. T 2 -weighted MRI was investigated in 18 patients. MET uptake did not correspond exactly with the hyperintensity areas on T 2 -weighted MRI in any patient. In 9 (50%) of 18 patients, MET uptake extended beyond the hyperintensity area on the T 2 -weighted MRI, and in 18 (100%), at least some hyperintensity on the T 2 -weighted MRI was located outside the MET enhancement area. MET uptake was detected up to 40 mm beyond the hyperintensity area on T 2 -weighted MRI. Conclusion: In operated patients with brain gliomas, the size and location of residual MET uptake differs considerably from abnormalities found on postoperative MRI. Because postoperative changes cannot be differentiated from residual tumor by MRI, MET-PET, with a greater specificity for tumor tissue, can help to outline the gross tumor volume with greater accuracy.