***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Background Neo-adjuvant chemoradiotherapy followed by surgery is the st and ard treatment with curative intent for oesophageal cancer patients , with 5-year overall survival rates up to 50 % . However , patients ’ quality of life is severely compromised by oesophagectomy , and eventually many patients die due to metastatic disease . Most solid tumours , including oesophageal cancer , contain hypoxic regions that are more resistant to chemoradiotherapy . The hypoxia-activated prodrug evofosfamide works as a DNA-alkylating agent under these hypoxic conditions , which directly kills hypoxic cancer cells and potentially minimizes resistance to conventional therapy . This drug has shown promising results in several clinical studies when combined with chemotherapy . Therefore , in this phase I study we investigate the safety of evofosfamide added to the chemoradiotherapy treatment of oesophageal cancer . Methods / Design A phase I , non-r and omized , single-centre , open-label , 3 + 3 trial with repeated hypoxia PET imaging , will test the safety of evofosfamide in combination with neo-adjuvant chemoradiotherapy in potentially resectable oesophageal adenocarcinoma patients . Investigated dose levels range from 120 mg/m2 to 340 mg/m2 . Evofosfamide will be administered one week before the start of chemoradiotherapy ( CROSS-regimen ) and repeated weekly up to a total of six doses . PET/CT acquisitions with hypoxia tracer 18F-HX4 will be made before and after the first administration of evofosfamide , allowing early assessment of changes in hypoxia , accompanied with blood sampling to measure hypoxia blood biomarkers . Oesophagectomy will be performed according to st and ard clinical practice .Higher grade and uncommon non-haematological , haematological , and post-operative toxicities are the primary endpoints according to the CTCAEv4.0 and Clavien-Dindo classifications . Secondary endpoints are reduction in hypoxic fraction based on 18F-HX4 imaging , pathological complete response , histopathological negative circumferential resection margin ( R0 ) rate , local and distant recurrence rate , and progression free and overall survival . Discussion This is the first clinical trial testing evofosfamide in combination with chemoradiotherapy . The primary objective is to determine the dose limiting toxicity of this combined treatment and herewith to define the maximum tolerated dose and recommended phase 2 dose for future clinical studies . The addition of non-invasive repeated hypoxia imaging ( ‘ window-of-opportunity ’ ) enables us to identify the biologically effective dose . We believe this approach could also be used for other hypoxia targeted drugs . Trial registration Clinical Trials.gov Identifier : NCT02598687 Background and purpose Increased tumour hypoxia is associated with a worse overall survival in patients with head and neck squamous cell carcinoma ( HNSCC ) . The aims of this study were to evaluate treatment-associated changes in [18F]HX4-PET , hypoxia-related blood biomarkers , and their interdependence . Material and methods [18F]HX4-PET/CT scans of 20 patients with HNSCC were acquired at baseline and after ±20Gy of radiotherapy . Within the gross-tumour-volumes ( GTV ; primary and lymph nodes ) , mean and maximum st and ardized uptake values , the hypoxic fraction ( HF ) and volume ( HV ) were calculated . Also , the changes in spatial uptake pattern were evaluated using [18F]HX4-PET/CT imaging . For all patients , the plasma concentration of CAIX , osteopontin and VEGF was assessed . Results At baseline , tumour hypoxia was detected in 69 % ( 22/32 ) of the GTVs . During therapy , we observed a significant decrease in all image parameters . The HF decreased from 21.7 ± 19.8 % ( baseline ) to 3.6 ± 10.0 % ( during treatment ; P < 0.001 ) . Only two patients had a HV > 1 cm3 during treatment , which was located for > 98 % within the baseline HV . During treatment , no significant changes in plasma CAIX or VEGF were observed , while osteopontin was increased . Conclusions [18F]HX4-PET/CT imaging allows monitoring changes in hypoxia during (chemo)radiotherapy whereas the blood biomarkers were not able to detect a treatment-associated decrease in hypoxia Purpose Hypoxia is an important factor influencing tumor progression and treatment efficacy . The aim of this study was to investigate the repeatability of hypoxia PET imaging with [18F]HX4 in patients with head and neck and lung cancer . Methods Nine patients with lung cancer and ten with head and neck cancer were included in the analysis ( NCT01075399 ) . Two sequential pretreatment [18F]HX4 PET/CT scans were acquired within 1 week . The maximal and mean st and ardized uptake values ( SUVmax and SUVmean ) were defined and the tumor-to- background ratios ( TBR ) were calculated . In addition , hypoxic volumes were determined as the volume of the tumor with a TBR > 1.2 ( HV1.2 ) . Bl and Altman analysis of the uptake parameters was performed and coefficients of repeatability were calculated . To evaluate the spatial repeatability of the uptake , the PET/CT images were registered and a voxel-wise comparison of the uptake was performed , providing a correlation coefficient . Results All parameters of [18F]HX4 uptake were significantly correlated between scans : SUVmax ( r = 0.958 , p < 0.001 ) , SUVmean ( r = 0.946 , p < 0.001 ) , TBRmax ( r = 0.962 , p < 0.001 ) and HV1.2 ( r = 0.995 , p < 0.001 ) . The relative coefficients of repeatability were 15 % ( SUVmean ) , 17 % ( SUVmax ) and 17 % ( TBRmax ) . Voxel-wise analysis of the spatial uptake pattern within the tumors provided an average correlation of 0.65 ± 0.14 . Conclusion Repeated hypoxia PET scans with [18F]HX4 provide reproducible and spatially stable results in patients with head and neck cancer and patients with lung cancer .  [18F]HX4 PET imaging can be used to assess the hypoxic status of tumors and has the potential to aid hypoxia-targeted treatments Background and purpose Noninvasive PET imaging of tumour hypoxia could help in the selection of those patients who could benefit from chemotherapy or radiation with specific antihypoxic treatments such as bioreductive drugs or hypoxic radiosensitizers .  In this phase I trial , we aim ed to determine the toxicity of [18F]HX4 , a member of the 2-nitroimidazole family , at different dose levels . The secondary aim was to analyse image quality related to the HX4 dose and the timing of imaging . Methods Patients with a histologically proven solid cancer without curative treatment options were eligible for this study . A study design with two dose steps was used in which a single dose of a maximum of 222 MBq ( step 1 ) or 444 MBq ( step 2 ) [18F]HX4 was injected . Toxicity was scored on day 0 and on days 3 and 7 after injection , according to the CTCAE 3.0 scoring system . PET/CT images of the largest tumour site were acquired 30 , 60 and 120 min after injection . Results Six patients with stage IV carcinoma were included , four with non-small-cell lung carcinoma , one with thymus carcinoma , and one with colon carcinoma .  No toxicity was observed in any of the patients at either dose level . The median tumour to muscle ratio 120 min after injection was 1.40 ( range 0.63–1.98 ) . Conclusion The findings of this study showed that [18F]HX4 PET imaging for the detection of hypoxia is not associated with any toxicity . Imaging was successful ; however , future trials are needed to determine the optimal image parameters BACKGROUND The role of neoadjuvant chemoradiotherapy in the treatment of patients with esophageal or esophagogastric-junction cancer is not well established . We compared chemoradiotherapy followed by surgery with surgery alone in this patient population . METHODS We r and omly assigned patients with resectable tumors to receive surgery alone or weekly administration of carboplatin ( doses titrated to achieve an area under the curve of 2 mg per milliliter per minute ) and paclitaxel ( 50 mg per square meter of body-surface area ) for 5 weeks and concurrent radiotherapy ( 41.4 Gy in 23 fractions , 5 days per week ) , followed by surgery . RESULTS From March 2004 through December 2008 , we enrolled 368 patients , 366 of whom were included in the analysis : 275 ( 75 % ) had adenocarcinoma , 84 ( 23 % ) had squamous-cell carcinoma , and 7 ( 2 % ) had large-cell undifferentiated carcinoma . Of the 366 patients , 178 were r and omly assigned to chemoradiotherapy followed by surgery  , and 188 to surgery alone . The most common major hematologic toxic effects in the chemoradiotherapy-surgery group were leukopenia ( 6 % ) and neutropenia ( 2 % ) ; the most common major nonhematologic toxic effects were anorexia ( 5 % ) and fatigue ( 3 % ) . Complete resection with no tumor within 1 mm of the resection margins ( R0 ) was achieved in 92 % of patients in the chemoradiotherapy-surgery group versus 69 % in the surgery group ( P<0.001 ) . A pathological complete response was achieved in 47 of 161 patients ( 29 % ) who underwent resection after chemoradiotherapy . Postoperative complications were similar in the two treatment groups , and in-hospital mortality was 4 % in both . Median overall survival was 49.4 months in the chemoradiotherapy-surgery group versus 24.0 months in the surgery group . Overall survival was significantly better in the chemoradiotherapy-surgery group ( hazard ratio , 0.657 ; 95 % confidence interval , 0.495 to 0.871 ; P=0.003 ) . CONCLUSIONS Preoperative chemoradiotherapy improved survival among patients with potentially curable esophageal or esophagogastric-junction cancer . The regimen was associated with acceptable adverse-event rates . ( Funded by the Dutch Cancer Foundation [ KWF Kankerbestrijding ] ; Netherl and s Trial Register number , NTR487 . ) BACKGROUND AND PURPOSE In a phase III trial in patients with advanced stage laryngeal carcinoma comparing ARCON ( accelerated radiotherapy with carbogen breathing and nicotinamide ) to accelerated radiotherapy alone ( AR ) the prognostic and predictive value of CAIX , a hypoxia-associated protein , was investigated . MATERIAL AND METHODS 261 Paraffin embedded tumor biopsies and 79 fresh frozen biopsies from patients entered in the trial were immunohistochemically stained for CAIX . CAIX-fraction and CAIX expression pattern were related to tumor control and patient survival . RESULTS Low CAIX-fraction was prognostic for worse regional control and overall survival in patients treated with AR . Patients with a low CAIX-fraction treated with ARCON had better regional control and metastasis-free survival compared to AR ( RC 97 % vs 71 % , p < 0.01 and MFS 92 % vs 69 % , p = 0.06 ) . Patients with a perinecrotic CAIX staining pattern had a significantly worse local control , metastasis-free and overall survival compared to patients with a diffuse pattern ( 65 % vs 84 % , p = 0.01 , 70 % vs 96 % , p < 0.01 and 42 % vs 71 % , p < 0.01 respectively ) , and this could not be improved with ARCON . After multivariate analysis CAIX pattern and N-stage emerged as significant predictors for metastasis-free survival and overall survival . CONCLUSIONS ARCON improves regional control and metastasis-free survival only in patients with low CAIX expression . The different patterns of CAIX expression suggest different mechanisms of upregulation and have important prognostic value 
    Output:
    
RESULTS In esophageal cancer , several (non-)invasive biomarkers for hypoxia could be identified .
Independent prognostic factors for treatment response include HIF-1α , CA IX , GLUT-1 overexpression and elevated uptake of the PET-tracer 18F-fluoroerythronitroimidazole ( 18F-FETNIM ) .
Hypoxia-associated molecular responses represents a clinical ly relevant phenomenon in esophageal cancer and detection of elevated levels of hypoxia-associated biomarkers and tends to be associated with poor treatment outcome ( i.e. , overall survival , disease-free survival , complete response and local control ) .