Hypoxic Subvolumes Research Articles

The significance of partial volume effect on the estimation of hypoxic tumour volume with [18F]FMISO PET/CT

BackgroundThe purpose of this study was to evaluate how a retrospective correction of the partial volume effect (PVE) in [18F]fluoromisonidazole (FMISO) PET imaging, affects the hypoxia discoverability within a gross tumour volume (GTV). This method is based on recovery coefficients (RC) and is tailored for low-contrast tracers such as FMISO. The first stage was the generation of the scanner’s RC curves, using spheres with diameters from 10 to 37 mm, and the same homogeneous activity concentration, positioned in lower activity concentration background. Six sphere-to-background contrast ratios were used, from 10.0:1, down to 2.0:1, in order to investigate the dependence of RC on both the volume and the contrast ratio. The second stage was to validate the recovery-coefficient correction method in a more complex environment of non-spherical lesions of different volumes and inhomogeneous activity concentration. Finally, we applied the correction method to a clinical dataset derived from a prospective imaging trial (DRKS00003830): forty nine head and neck squamous cell carcinoma (HNSCC) cases who had undergone FMISO PET/CT scanning for the quantification of tumour hypoxia before (W0), 2 weeks (W2) and 5 weeks (W5) after the beginning of radiotherapy. Here, PVE was found to cause an underestimation of the activity in small volumes with high FMISO signal.ResultsThe application of the proposed correction method resulted in a statistically significant increase of both the hypoxic subvolume (171% at W0, 691% at W2 and 4.60 × 103% at W5 with p < 0.001) and the FMISO standardised uptake value (SUV) (27% at W0, 21% at W2 and by 25% at W5 with p < 0.001) within the primary GTV.ConclusionsThe proposed PVE-correction method resulted in a statistically significant increase of the hypoxic fraction (HF) with p < 0.001 and demonstrated results in better agreement with published HF data for HNSCC. To summarise, the proposed RC-based correction method can be a useful tool for a retrospective compensation against PVE.

Absolute oxygen-guided radiation therapy improves tumor control in three preclinical tumor models.

Clinical attempts to find benefit from specifically targeting and boosting resistant hypoxic tumor subvolumes have been promising but inconclusive. While a first preclinical murine tumor type showed significant improved control with hypoxic tumor boosts, a more thorough investigation of efficacy from boosting hypoxic subvolumes defined by electron paramagnetic resonance oxygen imaging (EPROI) is necessary. The present study confirms improved hypoxic tumor control results in three different tumor types using a clonogenic assay and explores potential confounding experimental conditions. Three murine tumor models were used for multi-modal imaging and radiotherapy: MCa-4 mammary adenocarcinomas, SCC7 squamous cell carcinomas, and FSa fibrosarcomas. Registered T2-weighted MRI tumor boundaries, hypoxia defined by EPROI as pO2 ≤ 10 mmHg, and X-RAD 225Cx CT boost boundaries were obtained for all animals. 13 Gy boosts were directed to hypoxic or equal-integral-volume oxygenated tumor regions and monitored for regrowth. Kaplan-Meier survival analysis was used to assess local tumor control probability (LTCP). The Cox proportional hazards model was used to assess the hazard ratio of tumor progression of Hypoxic Boost vs. Oxygenated Boost for each tumor type controlling for experimental confounding variables such as EPROI radiofrequency, tumor volume, hypoxic fraction, and delay between imaging and radiation treatment. An overall significant increase in LTCP from Hypoxia Boost vs. Oxygenated Boost treatments was observed in the full group of three tumor types (p < 0.0001). The effects of tumor volume and hypoxic fraction on LTCP were dependent on tumor type. The delay between imaging and boost treatments did not have a significant effect on LTCP for all tumor types. This study confirms that EPROI locates resistant tumor hypoxic regions for radiation boost, increasing clonogenic LTCP, with potential enhanced therapeutic index in three tumor types. Preclinical absolute EPROI may provide correction for clinical hypoxia images using additional clinical physiologic MRI.

Quantitative MRI to Characterize Hypoxic Tumors in Comparison to FMISO PET/CT for Radiotherapy in Oropharynx Cancers

Intratumoral hypoxia is associated with a poor prognosis and poor response to treatment in head and neck cancers. Its identification would allow for increasing the radiation dose to hypoxic tumor subvolumes. 18F-FMISO PET imaging is the gold standard; however, quantitative multiparametric MRI could show the presence of intratumoral hypoxia. Thus, 16 patients were prospectively included and underwent 18F-FDG PET/CT, 18F-FMISO PET/CT, and multiparametric quantitative MRI (DCE, diffusion and relaxometry T1 and T2 techniques) in the same position before treatment. PET and MRI sub-volumes were segmented and classified as hypoxic or non-hypoxic volumes to compare quantitative MRI parameters between normoxic and hypoxic volumes. In total, 13 patients had hypoxic lesions. The Dice, Jaccard, and overlap fraction similarity indices were 0.43, 0.28, and 0.71, respectively, between the FDG PET and MRI-measured lesion volumes, showing that the FDG PET tumor volume is partially contained within the MRI tumor volume. The results showed significant differences in the parameters of SUV in FDG and FMISO PET between patients with and without measurable hypoxic lesions. The quantitative MRI parameters of ADC, T1 max mapping and T2 max mapping were different between hypoxic and normoxic subvolumes. Quantitative MRI, based on free water diffusion and T1 and T2 mapping, seems to be able to identify intra-tumoral hypoxic sub-volumes for additional radiotherapy doses.

The Impact of Heterogeneous Cell Density in Hypoxic Tumors Treated with Radiotherapy.

Hypoxia is frequently found in solid tumors and is known to increase the resistance to several kinds of treatment modalities including radiation therapy. Besides, the treatment response is also largely determined by the total number of clonogenic cells, i.e., cells with unlimited proliferative capacity. Depending on the duration of hypoxia, the rate of proliferation and hence also the clonogen density could be expected to differ in hypoxic compartments. The combination at the microscale between heterogeneous tumor oxygenation and clonogen density could therefore be crucial with respect to the outcome of a radiotherapy treatment. In this study it was investigated the impact of heterogeneous clonogen density on the outcome of stereotactic radiotherapy treatments of hypoxic tumors. A recently developed three-dimensional model for tissue vasculature and oxygenation was used to create realistic in silico tumors with heterogeneous oxygenation. Stereotactic radiotherapy treatments were simulated, and cell survival was calculated on a voxel-level accounting for the oxygenation. For a tumor with a diameter of 1 cm and a baseline clonogenic density of 107/cm3 for the normoxic subvolume, when the relative density for the hypoxic cells drops by a factor of 10 the tumor control probability (TCP) decreases by about 10% when relatively small hypoxic volumes and few fractions are considered; longer treatments tend to level out the results. With increasing size of the hypoxic subvolume, the TCP decreased overall as expected, and the difference in TCP between a homogeneous and a heterogeneous distribution of cells increased. The results demonstrate a delicate interplay between the heterogeneous distribution of tumor oxygenation and clonogenic cells that could significantly impact on the treatment outcome of radiotherapy.

Hyperhydration of Cancers: A Characteristic Biophysical Trait Strongly Increasing O2, CO2, Glucose and Lactate Diffusivities, and Improving Thermophysical Properties of Solid Malignancies.

Cancers are complex, heterogeneous, dynamic and aggressive diseases exhibiting a series of characteristic biophysical traits which complement the original biological hallmarks of cancers favouring progressive growth, metastasis, and contributing to immune evasion and treatment resistance. One of the prevalent differences between most solid tumors and their corresponding, healthy tissues is a significantly higher water content (hyperhydration) in cancers. As a consequence, cancers have distinctly higher (Fick's) diffusion coefficients D [cm2s-1] for the respiratory gases O2 and CO2, the key substrate glucose, and for the oncometabolite lactate. In addition, cancers have (a) clearly increased specific heat capacities cp [Jg-1K-1], thus representing high-capacity-tissues upon therapeutic heating induced by electromagnetic irradiation, and (b) higher thermal conductivities k [Wm-1K-1], i.e., increased abilities to conduct heat. Therefore, in diffusion analyses (e.g., when describing critical O2 and glucose supplies or CO2 removal, and the development of hypoxic subvolumes) and for modeling temperature distributions in hyperthermia treatment planning, these specific cancer-related data must be considered in order to reliably reflect oncologic thermo-radiotherapy settings.

Immunohistochemical analyses of paraffin-embedded sections after primary surgery or trimodality treatment in esophageal carcinoma

BackgroundThe microscopic tumor extension before, during or after radiochemotherapy (RCHT) and its correlation with the tumor microenvironment (TME) are presently unknown. This information is, however, crucial in the era of image-guided, adaptive high-precision photon or particle therapy. Materials and methodsIn this pilot study, we analyzed formalin-fixed paraffin-embedded (FFPE) tumor resection specimen from patients with histologically confirmed squamous cell carcinoma (SCC; n = 10) or adenocarcinoma (A; n = 10) of the esophagus, having undergone neoadjuvant radiochemotherapy followed by resection (NRCHT + R) or resection (R)]. FFPE tissue sections were analyzed by immunohistochemistry regarding tumor hypoxia (HIF-1α), proliferation (Ki67), immune status (PD1), cancer cell stemness (CXCR4), and p53 mutation status. Marker expression in HIF-1α subvolumes was part of a sub-analysis. Statistical analyses were performed using one-sided Mann-Whitney tests and Bland-Altman analysis. ResultsIn both SCC and AC patients, the overall percentages of positive tumor cells among the five TME markers, namely HIF-1α, Ki67, p53, CXCR4 and PD1 after NRCHT were lower than in the R cohort. However, only PD1 in SCC and Ki67 in AC showed significant association (Ki67: p = 0.03, PD1: p = 0.02). In the sub-analysis of hypoxic subvolumes among the AC patients, the percentage of positive tumor cells within hypoxic regions were statistically significantly lower in the NRCHT than in the R cohort across all the markers except for PD1. ConclusionIn this pilot study, we showed changes in the TME induced by NRCHT in both SCC and AC. These findings will be correlated with microscopic tumor extension measurements in a subsequent cohort of patients.

Radiobiological and Treatment-Related Aspects of Spatially Fractionated Radiotherapy.

The continuously evolving field of radiotherapy aims to devise and implement techniques that allow for greater tumour control and better sparing of critical organs. Investigations into the complexity of tumour radiobiology confirmed the high heterogeneity of tumours as being responsible for the often poor treatment outcome. Hypoxic subvolumes, a subpopulation of cancer stem cells, as well as the inherent or acquired radioresistance define tumour aggressiveness and metastatic potential, which remain a therapeutic challenge. Non-conventional irradiation techniques, such as spatially fractionated radiotherapy, have been developed to tackle some of these challenges and to offer a high therapeutic index when treating radioresistant tumours. The goal of this article was to highlight the current knowledge on the molecular and radiobiological mechanisms behind spatially fractionated radiotherapy and to present the up-to-date preclinical and clinical evidence towards the therapeutic potential of this technique involving both photon and proton beams.

The value of plasma hypoxia markers for predicting imaging-based hypoxia in patients with head-and-neck cancers undergoing definitive chemoradiation

BackgroundTumor hypoxia worsens the prognosis of head-and-neck squamous cell carcinoma (HNSCC) patients, and plasma hypoxia markers may be used as biomarkers for radiotherapy personalization. We therefore investigated the role of the hypoxia-associated plasma proteins osteopontin, galectin-3, vascular endothelial growth factor (VEGF) and connective tissue growth factor (CTGF) as surrogate markers for imaging-based tumor hypoxia. MethodsSerial blood samples of HNSCC patients receiving chemoradiation within a prospective trial were analyzed for osteopontin, galectin-3, VEGF and CTGF concentrations. Tumor hypoxia was quantified in treatment weeks 0, 2 and 5 using [18F]FMISO PET/CT. The association between PET-defined hypoxia and the plasma markers was determined using Pearson’s correlation analyses. Receiver-operating characteristic analyses were conducted to reveal the diagnostic value of the hypoxia markers. ResultsBaseline osteopontin (r = 0.579, p < 0.01) and galectin-3 (r = 0.429, p < 0.05) correlated with the hypoxic subvolume (HSV) prior to radiotherapy, whereas VEGF (r = 0.196, p = 0.36) and CTGF (r = 0.314, p = 0.12) showed no association. Patients with an HSV > 1 mL in week 2 exhibited increased VEGF (p < 0.05) and CTGF (p < 0.05) levels in week 5. Pretherapeutic osteopontin levels were higher in patients exhibiting residual hypoxia at the end of treatment (104.7 vs. 60.8 ng/mL, p < 0.05) and could therefore predict residual hypoxia (AUC = 0.821, 95% CI 0.604–1.000, p < 0.05). ConclusionIn this exploratory analysis, osteopontin correlated with the initial HSV and with residual tumor hypoxia; therefore, there may be a rationale to study hypoxic modification based on osteopontin levels. However, as plasma hypoxia markers do not correspond to any spatial information of tumor hypoxia, they have limitations regarding the replacement of [18F]FMISO PET-based focal treatments. The results need to be validated in larger patient cohorts to draw definitive conclusions.

Imaging of Tumor Hypoxia With 18F-EF5 PET/MRI in Cervical Cancer.

The aim of this study was to evaluate the distribution of hypoxia using 18F-EF5 as a hypoxia tracer in cervical cancer patients with PET/MRI. We investigated the association between this 18F-EF5-PET tracer and the immunohistochemical expression of endogenous hypoxia markers: HIF1α, CAIX, and GLUT1. Nine patients with biopsy-proven primary squamous cell cervix carcinoma (FIGO 2018 radiological stages IB1-IIIC2r) were imaged with dual tracers 18F-EF5 and 18F-FDG using PET/MRI (Int J Gynaecol Obstet. 2019;145:129-135). 18F-EF5 images were analyzed by calculating the tumor-to-muscle ratio to determine the hypoxic tissue (T/M ratio >1.5) and further hypoxic subvolume (HSV) and percentage hypoxic area. These 18F-EF5 hypoxic parameters were correlated with the size and localization of tumors in 18F-FDG PET/MRI and the results of hypoxia immunohistochemistry. All primary tumors were clearly 18F-FDG and 18F-EF5 PET positive and heterogeneously hypoxic with multiple 18F-EF5-avid areas in locally advanced cancer and single areas in clinically stage I tumors. The location of hypoxia was detected mainly in the periphery of tumor. Hypoxia parameters 18F-EF5 max T/M ratio and HSV in primary tumors correlated independently with the advanced stage (P = 0.036 and P = 0.040, respectively), and HSV correlated with the tumor size (P = 0.027). The location of hypoxia in 18F-EF5 imaging was confirmed with a higher hypoxic marker expression HIF1α and CAIX in tumor fresh biopsies. The 18F-EF5 imaging has promising potential in detecting areas of tumor hypoxia in cervical cancer.

Interleukin-6 as surrogate marker for imaging-based hypoxia dynamics in patients with head-and-neck cancers undergoing definitive chemoradiation—results from a prospective pilot trial

PurposeIntratumoral hypoxia increases resistance of head-and-neck squamous cell carcinoma (HNSCC) to radiotherapy. [18F]FMISO PET imaging enables noninvasive hypoxia monitoring, though requiring complex logistical efforts. We investigated the role of plasma interleukin-6 (IL-6) as potential surrogate parameter for intratumoral hypoxia in HNSCC using [18F]FMISO PET/CT as reference.MethodsWithin a prospective trial, serial blood samples of 27 HNSCC patients undergoing definitive chemoradiation were collected to analyze plasma IL-6 levels. Intratumoral hypoxia was assessed in treatment weeks 0, 2, and 5 using [18F]FMISO PET/CT imaging. The association between PET-based hypoxia and IL-6 was examined using Pearson’s correlation and multiple regression analyses, and the diagnostic power of IL-6 for tumor hypoxia response prediction was determined with receiver-operating characteristic analyses.ResultsMean IL-6 concentrations were 15.1, 19.6, and 31.0 pg/mL at baseline, week 2 and week 5, respectively. Smoking (p=0.050) and reduced performance status (p=0.011) resulted in higher IL-6 levels, whereas tumor (p=0.427) and nodal stages (p=0.334), tumor localization (p=0.439), and HPV status (p=0.294) had no influence. IL-6 levels strongly correlated with the intratumoral hypoxic subvolume during treatment (baseline: r=0.775, p<0.001; week 2: r=0.553, p=0.007; week 5: r=0.734, p<0.001). IL-6 levels in week 2 were higher in patients with absent early tumor hypoxia response (p=0.016) and predicted early hypoxia response (AUC=0.822, p=0.031). Increased IL-6 levels at week 5 resulted in a trend towards reduced progression-free survival (p=0.078) and overall survival (p=0.013).ConclusionPlasma IL-6 is a promising surrogate marker for tumor hypoxia dynamics in HNSCC patients and may facilitate hypoxia-directed personalized radiotherapy concepts.Trial registrationThe prospective trial was registered in the German Clinical Trial Register (DRKS00003830). Registered 20 August 2015

Simulated dose painting of hypoxic sub-volumes in pancreatic cancer stereotactic body radiotherapy

Dose painting of hypoxic tumour sub-volumes using positron-emission tomography (PET) has been shown to improve tumour control in silico in several sites, predominantly head and neck and lung cancers. Pancreatic cancer presents a more stringent challenge, given its proximity to critical gastro-intestinal organs-at-risk (OARs), anatomic motion, and impediments to reliable PET hypoxia quantification. A radiobiological model was developed to estimate clonogen survival fraction (SF), using 18F-fluoroazomycin arabinoside PET (FAZA PET) images from ten patients with unresectable pancreatic ductal adenocarcinoma to quantify oxygen enhancement effects. For each patient, four simulated five-fraction stereotactic body radiotherapy (SBRT) plans were generated: (1) a standard SBRT plan aiming to cover the planning target volume with 40 Gy, (2) dose painting plans delivering escalated doses to a maximum of three FAZA-avid hypoxic sub-volumes, (3) dose painting plans with simulated spacer separating the duodenum and pancreatic head, and (4), plans with integrated boosts to geometric contractions of the gross tumour volume (GTV). All plans saturated at least one OAR dose limit. SF was calculated for each plan and sensitivity of SF to simulated hypoxia quantification errors was evaluated. Dose painting resulted in a 55% reduction in SF as compared to standard SBRT; 78% with spacer. Integrated boosts to hypoxia-blind geometric contractions resulted in a 41% reduction in SF. The reduction in SF for dose-painting plans persisted for all hypoxia quantification parameters studied, including registration and rigid motion errors that resulted in shifts and rotations of the GTV and hypoxic sub-volumes by as much as 1 cm and 10 degrees. Although proximity to OARs ultimately limited dose escalation, with estimated SFs (∼10−5) well above levels required to completely ablate a ∼10 cm3 tumour, dose painting robustly reduced clonogen survival when accounting for expected treatment and imaging uncertainties and thus, may improve local response and associated morbidity.

18F-FMISO-PET Hypoxia Monitoring for Head-and-Neck Cancer Patients: Radiomics Analyses Predict the Outcome of Chemo-Radiotherapy.

Simple SummaryIn this study, we monitored FMISO-hypoxia during chemo-radiotherapy (CRT) in head-and-neck cancer patients and we aimed to develop a radiomics model for prediction of treatment outcome. The protocol for the prospective patient cohort (N = 35) involved FMISO-PET/CT imaging at three time-points during treatment (weeks 0, 2 and 5). FMISO-hypoxia monitoring was quantified in terms of variations in the size, in the location and in the radiomics features (delta radiomics) of the hypoxia subvolume within the tumor. Local recurrence, distant metastasis, overall survival and progression free survival were employed for the characterization of CRT outcome.Tumor hypoxia is associated with radiation resistance and can be longitudinally monitored by 18F-fluoromisonidazole (18F-FMISO)-PET/CT. Our study aimed at evaluating radiomics dynamics of 18F-FMISO-hypoxia imaging during chemo-radiotherapy (CRT) as predictors for treatment outcome in head-and-neck squamous cell carcinoma (HNSCC) patients. We prospectively recruited 35 HNSCC patients undergoing definitive CRT and longitudinal 18F-FMISO-PET/CT scans at weeks 0, 2 and 5 (W0/W2/W5). Patients were classified based on peritherapeutic variations of the hypoxic sub-volume (HSV) size (increasing/stable/decreasing) and location (geographically-static/geographically-dynamic) by a new objective classification parameter (CP) accounting for spatial overlap. Additionally, 130 radiomic features (RF) were extracted from HSV at W0, and their variations during CRT were quantified by relative deviations (∆RF). Prediction of treatment outcome was considered statistically relevant after being corrected for multiple testing and confirmed for the two 18F-FMISO-PET/CT time-points and for a validation cohort. HSV decreased in 64% of patients at W2 and in 80% at W5. CP distinguished earlier disease progression (geographically-dynamic) from later disease progression (geographically-static) in both time-points and cohorts. The texture feature low grey-level zone emphasis predicted local recurrence with AUCW2 = 0.82 and AUCW5 = 0.81 in initial cohort (N = 25) and AUCW2 = 0.79 and AUCW5 = 0.80 in validation cohort. Radiomics analysis of 18F-FMISO-derived hypoxia dynamics was able to predict outcome of HNSCC patients after CRT.

Development of a PET/EPRI combined imaging system for assessing tumor hypoxia

Precise quantitative delineation of tumor hypoxia is essential in radiation therapy treatment planningto improve the treatment efficacy by targeting hypoxic sub-volumes.We developed a combined imaging system of positron emission tomography (PET) and electron para-magnetic resonance imaging (EPRI) of molecular oxygento investigate the accuracy of PET imaging in assessing tumor hypoxia.The PET/EPRI combined imaging system aims to use EPRI to precisely measure the oxygen partial pressure in tissues.This will evaluate the validity of PET hypoxic tumor imaging by (near) simultaneously acquired EPRI as ground truth. The combined imaging system was constructed by integrating a small animal PET scanner (inner ring diameter 62 mm and axial field of view 25.6 mm)and an EPRI subsystem (field strength 25 mT and resonant frequency 700 MHz).The compatibility between the PET and EPRI subsystems were tested with both phantom and animal imaging.Hypoxic imaging on a tumor mouse model using 18F-fluoromisonidazole radio-tracerwas conducted with the developed PET/EPRI system.We report the development and initial imaging results obtained from the PET/EPRI combined imaging system.

Patient-Derived Nasopharyngeal Cancer Organoids for Disease Modeling and Radiation Dose Optimization.

Effective radiation treatment (RT) for recurrent nasopharyngeal cancers (NPC), featuring an intrinsic hypoxic sub-volume, remains a clinical challenge. Lack of disease‐specific in-vitro models of NPC, together with difficulties in establishing patient derived xenograft (PDX) models, have further hindered development of personalized therapeutic options. Herein, we established two NPC organoid lines from recurrent NPC PDX models and further characterized and compared these models with original patient tumors using RNA sequencing analysis. Organoids were cultured in hypoxic conditions to examine the effects of hypoxia and radioresistance. These models were then utilized to determine the radiobiological parameters, such as α/β ratio and oxygen enhancement ratio (OER), characteristic to radiosensitive normoxic and radioresistant hypoxic NPC, using simple dose-survival data analytic tools. The results were further validated in-vitro and in-vivo, to determine the optimal boost dose and fractionation regimen required to achieve effective NPC tumor regression. Despite the differences in tumor microenvironment due to the lack of human stroma, RNA sequencing analysis revealed good correlation of NPC PDX and organoid models with patient tumors. Additionally, the established models also mimicked inter-tumoral heterogeneity. Hypoxic NPC organoids were highly radioresistant and had high α/β ratio compared to its normoxic counterparts. In-vitro and in-vivo fractionation studies showed that hypoxic NPC was less sensitive to RT fractionation scheme and required a large bolus dose or 1.4 times of the fractionated dose that was effective against normoxic cells in order to compensate for oxygen deficiency. This study is the first direct experimental evidence to predict optimal RT boost dose required to cause sufficient damage to recurrent hypoxic NPC tumor cells, which can be further used to develop dose-painting algorithms in clinical practice.

PET/CT in the Evaluation of Hypoxia for Radiotherapy Planning in Head and Neck Tumors: Systematic Literature Review.

PET/CT combines imaging at the molecular level along with imaging at the anatomic level, which, with the administration of a hypoxia-sensitive radiopharmaceutical, allows evaluation of tissue oxygenation. Methods: This work consisted of a systematic literature review that included websites, books, and articles dated from July 1997 to December 2019. The aim was to identify the PET radiopharmaceuticals best suited to the detection of cell hypoxia and to recognize the benefits for planning intensity-modulated radiation therapy (IMRT) and volumetric arc therapy (VMAT). Results: Hypoxia affects the likelihood of cure for head and neck tumors, reducing the success rate. Radiopharmaceuticals such as 18F-fluoromisonidazole, 18F-fluoroerythronitromidazole, and 18F-HX4 (18F-3-fluoro-2-(4-((2-nitro-1H-imidazol-1-yl)methyl)-1H-1,2,3-triazol-1-yl)propan-1-ol) allow the delineation of hypoxic subvolumes within the target volume to optimize IMRT/VMAT. Conclusion: Identification of hypoxic areas with PET/CT imaging and use of subsequent IMRT/VMAT allows for possible escalation of radiation dose in radioresistant subvolumes, with a consequent decrease in relapses and an increased likelihood of disease-free survival.

PO-1695: The utility of multiparametric MRI to characterize hypoxic tumor subvolumes compared to FMISO PET/CT

PO-1695: The utility of multiparametric MRI to characterize hypoxic tumor subvolumes compared to FMISO PET/CT

Influence of FAZA PET hypoxia and HPV-status for the outcome of head and neck squamous cell carcinoma (HNSCC) treated with radiotherapy: Long-term results from the DAHANCA 24 trial (NCT01017224)

PurposeHypoxic tumor volumes can be visualized with 18F-FAZA PET/CT. In head and neck squamous cell carcinoma (HNSCC), hypoxia is important for the clinical outcome after primary radiotherapy (RT). The outcome is furthermore heavily influenced by the HPV/p16-positivity of oropharyngeal tumors (OPCp16+ tumors). The study purposes were (1) to report on locoregional failures within five years after primary RT in a prospective cohort stratified by both HPV/p16-status and PET hypoxia and (2) to characterize the failure site and the spatial association to PET hypoxia. Material and methodsFrom 2009 to 2011, 38 patients with non-metastatic SCC of the larynx, oro-, hypo- and nasopharynx completing primary RT were included in the prospective DAHANCA 24 trial (NCT01017224). Fifteen patients had OPCp16+ tumors. All were imaged with a static FAZA PET/CT prior to treatment. The hypoxia threshold was determined by a tumor-to-muscle ratio (TMR) of 1.6. Recurrences were documented histologically. Imaging of the recurrence was deformable fused with the pre-treatment FAZA PET/CT. The spatial information of recurrence- and hypoxic volumes were compared visually. ResultsSixteen patients had more hypoxic tumors (high tracer uptake, TMR ≥1.6) before treatment (42%). With a median follow-up of 7.8 years, nine locoregional recurrences were observed, of which seven were in patients with high-uptake tumors (44% and 9%, respectively, HR 5.8 [1.2–28.2]). The risk of locoregional recurrence was highest among patients with more hypoxic, non-OPCp16+ tumors (57% [21–94%]), with a risk difference of 45% [4–86%], when comparing to less hypoxic, non-OPCp16+ tumors. Eight patients had sufficient imaging of the recurrence for co-registration with the FAZA PET/CT. Six had hypoxic primary tumors, and in two, the recurrence was overlapping the baseline hypoxic subvolume. ConclusionHNSCC demonstrating a TMR ≥1.6 at baseline is significantly associated with treatment failure after primary RT. In addition to HPV/p16-status, FAZA PET/CT has potential for the selection of tumors requiring treatment intensification.

The utility of multiparametric MRI to characterize hypoxic tumor subvolumes in comparison to FMISO PET/CT. Consequences for diagnosis and chemoradiation treatment planning in head and neck cancer

Background and PurposeHypoxia is an essential metabolic marker that determines chemo- and radiation resistance in head-and-neck squamous cell carcinoma (HNSCC) patients. Our exploratory analysis aimed to identify multiparametric MRI (mpMRI) parameters linked to hypoxia that might be used as surrogate for [18F]FMISO-PET in diagnosis and chemoradiation treatment (CRT) of HNSCC. Materials and Methods21 patients undergoing definitive CRT for HNSCC were prospectively imaged with serial [18F]FMISO-PET and 3 Tesla mpMRI for T1- and T2-weighted and dynamic contrast-enhanced perfusion and diffusion-weighted measurements (ktrans, ve, kep, ADC) in weeks 0, 2 and 5 and FDG-PET in week 0. [18F]FMISO-PET-derived hypoxic subvolumes (HSV) and complementary non-hypoxic subvolumes (nonHSV) were created for tumor and lymph nodes and projected on the mpMRI scans after PET/MRI co-registration. MpMRI and [18F]FMISO-PET parameters within HSVs and nonHSVs were statistically compared. ResultsFMISO-PET-based HSVs of the primary tumors on MRI were characterized by lower ADC at all time points (p = 0.012 at baseline; p = 0.015 in week 2) and reduced interstitial space volume fraction ve and perfusion ktrans at baseline (p = 0.006, p = 0.047) compared to nonHSVs. Hypoxic lymph nodes were characterized by significantly lower ADC values at baseline (p = 0.039), but not at later time points and a reduction in ktrans-based perfusion at week 2 (p = 0.018). ConclusionMpMRI parameters differ significantly between hypoxic and non-hypoxic tumor regions, defined on FMISO-PET/CT as gold standard and might represent surrogate markers for tumor hypoxia. These findings suggest that mpMRI may be useful in the future as a surrogate modality for hypoxia imaging in order to personalize CRT.

Hypoxia Induced by Vascular Damage at High Doses Could Compromise the Outcome of Radiotherapy.

This study investigated the impact of temporary vascular collapse on tumour control probability (TCP) in stereotactic body radiotherapy (SBRT), taking into account different radiosensitivities of chronically and acutely hypoxic cells. Three-dimensional tumours with heterogeneous oxygenation were simulated assuming different fractions of collapsed vessels at every treatment fraction. The modelled tumours contained a chronically hypoxic subvolume of 30-60% of the tumour diameter, and a hypoxic fraction ≤5 mm Hg of 30-50%. The rest of the tumours were well-oxygenated at the start of the simulated treatment. For all simulated cases, the largest reduction in TCP from 97% to 2% was found in a tumour with a small chronically hypoxic core treated with 60 Gy in eight fractions and assuming a treatment-induced vascular collapse of 35% in the well-oxygenated region. The timing of SBRT fractions should be considered together with the tumour oxygenation to avoid loss of TCP in SBRT.

Impact of SBRT fractionation in hypoxia dose painting - Accounting for heterogeneous and dynamic tumor oxygenation.

Tumor hypoxia, often found in nonsmall cell lung cancer (NSCLC), implies an increased resistance to radiotherapy. Pretreatment assessment of tumor oxygenation is, therefore, warranted in these patients, as functional imaging of hypoxia could be used as a basis for dose painting. This study aimed at investigating the feasibility of using a method for calculating the dose required in hypoxic subvolumes segmented on 18 F-HX4 positron emission tomography (PET) imaging of NSCLC. Positron emission tomography imaging data based on the hypoxia tracer 18 F-HX4 of 19 NSCLC patients were included in the study. Normalized tracer uptake was converted to oxygen partial pressure (pO2 ) and hypoxic target volumes (HTVs) were segmented using a threshold of 10mmHg. Uniform doses required to overcome the hypoxic resistance in the target volumes were calculated based on a previously proposed method taking into account the effect of interfraction reoxygenation, for fractionation schedules ranging from extremely hypofractionated stereotactic body radiotherapy (SBRT) to conventionally fractionated radiotherapy. Gross target volumes ranged between 6.2 and 859.6cm3 , and the hypoxic fraction<10mmHg between 1.2% and 72.4%. The calculated doses for overcoming the resistance of cells in the HTVs were comparable to those currently prescribed in clinical practice as well as those previously tested in feasibility studies on dose escalation in NSCLC. Depending on the size of the HTV and the distribution of pO2 , HTV doses were calculated as 43.6-48.4Gy for a three-fraction schedule, 51.7-57.6Gy for five fractions, and 59.5-66.4Gy for eight fractions. For patients in whom the HTV pO2 distribution was more favorable, a lower dose was required despite a bigger volume. Tumor control probability was lower for single-fraction schedules, while higher levels of tumor control probability were found for schedules employing several fractions. The method to account for heterogeneous and dynamic hypoxia in target volume segmentation and dose prescription based on 18 F-HX4-PET imaging appears feasible in NSCLC patients. The distribution of oxygen partial pressure within HTV could impact the required prescribed dose more than the size of the volume.