Hypoxic Tumor Volume Research Articles

Optimal timing of fluorine-18-fluoromisonidazole positron emission tomography/computed tomography for assessment of tumor hypoxia in patients with head and neck squamous cell carcinoma.

The aim of this study was to identify the optimal timing of fluorine-18-fluoromisonidazole (F-MISO) PET/CT imaging to assess hypoxia in patients with head and neck squamous cell carcinoma. Eighteen patients underwent pretreatment F-MISO PET/CT imaging after providing written informed consent. PET scans were acquired at 1, 3, and 5 h after injection of the radionuclide. The mean standardized uptake value (SUV) within a spherical region of interest placed on the contralateral neck musculature at the level of the largest tumor dimension was labeled as background. A value 1.5 times the background was deemed the threshold for significant hypoxia. Using this threshold, volumetric regions of interest encompassing the tumor were placed and hypoxic tumor volume (HTV) was generated for the primary tumor. Repeated-measures analysis of variance was used to compare the F-MISO PET/CT metrics across the three time-points. The volume of the primary tumor was also correlated with HTV. The mean SUV of the background decreased consistently over time, resulting in increased focality of F-MISO uptake in the tumor tissues. Analysis of variance showed statistically significant differences in the mean SUV measurements of the background between the 1-h and the 3-h time-points (P=0.034) as well as the 1-h and the 5-h time-points (P=0.034). In parallel, the mean HTV increased from 1.72 cm at 1 h after injection to 6.52 cm at 3 h and further to 7.24 cm at 5 h, with a statistically significant difference between the 1-h and the 3-h scans (P=0.023) and the 1-h and the 5-h scans (P=0.023). There was a moderately good positive correlation between gross tumor volume on planning computed tompography (CT) and HTV at 3 h on the F-MISO scan (Pearson's correlation co-efficient 'r'=+0.753; P<0.0001). The contrast resolution of F-MISO PET/CT scans in head and neck squamous cell carcinoma is suboptimal with early image acquisition, but improves significantly after delayed imaging. Increasing volume of tumor at the primary site is associated with an increase in hypoxia.

High Single Doses of Radiation May Induce Elevated Levels of Hypoxia in Early-Stage Non-Small Cell Lung Cancer Tumors

Tumor hypoxia correlates with treatment failure in patients undergoing conventional radiation therapy. However, no published studies have investigated tumor hypoxia in patients undergoing stereotactic body radiation therapy (SBRT). We aimed to noninvasively quantify the tumor hypoxic volume (HV) in non-small cell lung cancer (NSCLC) tumors to elucidate the potential role of tumor vascular response and reoxygenation at high single doses. Six SBRT-eligible patients with NSCLC tumors >1cm were prospectively enrolled in an institutional review board-approved study. Dynamic positron emission tomography images were acquired at 0 to 120minutes, 150 to 180minutes, and 210 to 240minutes after injection of 18F-fluoromisonidazole. Serial imaging was performed prior to delivery of 18Gy and at approximately 48hours and approximately 96hours after SBRT. Tumor HVs were quantified using the tumor-to-blood ratio (>1.2) and rate of tracer influx (>0.0015mL·min·cm-3). An elevated and in some cases persistent level of tumor hypoxia was observed in 3 of 6 patients. Two patients exhibited no detectable baseline tumor hypoxia, and 1 patient with high baseline hypoxia only completed 1 imaging session. On the basis of the tumor-to-blood ratio, in the remaining 3 patients, tumor HVs increased on day 2 after 18Gy and then showed variable responses on day 4. In the 3 of 6 patients with detectable hypoxia at baseline, baseline tumor HVs ranged between 17% and 24% (mean, 21%), and HVs on days 2 and 4 ranged between 33% and 45% (mean, 40%) and between 18% and 42% (mean, 28%), respectively. High single doses of radiation delivered as part of SBRT may induce an elevated and in some cases persistent state of tumor hypoxia in NSCLC tumors. Hypoxia imaging with 18F-fluoromisonidazole positron emission tomography should be used in a larger cohort of NSCLC patients to determine whether elevated tumor hypoxia is predictive of treatment failure in SBRT.

Abstract 4228: Imaging and targeting of hypoxic microenvironments in prostate cancer

Abstract Cancer cells display an adaptive response to hypoxia through the activation of several genes mediated by the binding of hypoxia inducible factors (HIFs) to hypoxia response elements (HRE) in the promoter region of target gene that results in their increased transcription [1]. HIFs promote key steps in tumorigenesis, including angiogenesis, metabolism, proliferation, metastasis, and differentiation [1]. Bacterial or yeast cytosine deaminase (yCD) converts the nontoxic prodrug 5-fluorocytosine (5-FC) to the anti-cancer drug 5-fluorouracil (5-FU) that is widely used in cancer treatment [2]. Using a lentivirus approach, we established controlled expression of yCD by HRE in prostate cancer cells (PC-3). These cells also report on HIF-1α expression with regulated luciferase (Luc) expression, allowing detection of hypoxia, and the generation of 5-FU from 5-FC by yCD in the presence of hypoxia. Transduction efficiency and reporter activity in response to hypoxia was evaluated by performing luciferase assays, and bioluminescence imaging (BLI) of cells in vitro or in vivo using a Xenogen IVIS Spectrum system. Cell viability in vitro in response to hypoxia in the presence of 5-FC was assessed by MTS assay. In vivo studies were performed by inoculating 2×10⁁6 PC-3-HRE-Luc cells and PC-3-HRE-yCD+Luc cells on either flank of 5-week-old male severely combined immune deficient (SCID) mice. BLI was performed once tumors reached ∼200mm3 followed by 5-FC injection through the tail vein (200mg/kg) and intraperitoneally (250mg/kg). BLI was performed 3 days after the first 5-FC injection and continued through the treatment protocol. At the end of the treatment protocol, tumors were excised, and a part of the tumor was processed for immunohistochemistry. Bioluminescence was detected in both PC3-HRE-Luc and PC-3-HRE-yCD+Luc cells only in response to the hypoxia mimetic cobalt chloride or hypoxia (1% O2) confirming the regulation of luciferase by hypoxia and activation of CD. Expression of yCD and its ability to convert the prodrug 5-FC to 5-FU, with increased cell kill was evident under hypoxia. In vivo, engineered PC-3-HRE-yCD+Luc cells reported hypoxia, and showed significant reduction of hypoxic regions and tumor volume. Morphologically, PC-3-HRE-yCD+Luc tumors exhibited extensive necrosis. We are currently evaluating the effects of eliminating hypoxic cancer cells on distant metastasis as well as on aggressive subpopulations such as cancer stem cells in the primary tumor.

Clinical implications of hypoxia biomarker expression in head and neck squamous cell carcinoma: a systematic review.

Awareness increases that the tumor biology influences treatment outcome and prognosis in cancer. Tumor hypoxia is thought to decrease sensitivity to radiotherapy and some forms of chemotherapy. Presence of hypoxia may be assessed by investigating expression of endogenous markers of hypoxia (EMH) using immunohistochemistry (IHC). In this systematic review we investigated the effect of EMH expression on local control and survival according to treatment modality in head and neck cancer (head and neck squamous cell carcinoma [HNSCC]). A search was performed in MEDLINE and EMBASE. Studies were eligible for inclusion that described EMH expression in relation to outcome in HNSCC patients. Quality was assessed using the Quality in Prognosis Studies (QUIPS) tool. Hazard ratios for locoregional control and survival were extracted. Forty studies of adequate quality were included. HIF-1a, HIF-2a, CA-IX, GLUT-1, and OPN were identified as the best described EMHs. With exception of HIF-2a, all EMHs were significantly related to adverse outcome in multiple studies, especially in studies where patients underwent single-modality treatment. Positive expression was often correlated with adverse clinical characteristics, including disease stage and differentiation grade. In summary, EMH expression was common in HNSCC patients and negatively influenced their prognosis. Future studies should investigate the effect of hypoxia-modified treatment schedules in patients with high In summary, EMH expression. These may include ARCON, treatment with nimorazole, or novel targeted therapies directed at hypoxic tissue. Also, the feasibility of surgical removal of the hypoxic tumor volume prior to radiotherapy should be investigated.

EP-1628: Commissioning of 18F-FMISO PET-CT circuit to determining the hypoxic tumor volume in lung cancer

EP-1628: Commissioning of 18F-FMISO PET-CT circuit to determining the hypoxic tumor volume in lung cancer

In vivo quantification of hypoxic and metabolic status of NSCLC tumors using [18F]HX4 and [18F]FDG-PET/CT imaging.

Increased tumor metabolism and hypoxia are related to poor prognosis in solid tumors, including non-small cell lung cancer (NSCLC). PET imaging is a noninvasive technique that is frequently used to visualize and quantify tumor metabolism and hypoxia. The aim of this study was to perform an extensive comparison of tumor metabolism using 2[(18)F]fluoro-2-deoxy-d-glucose (FDG)-PET and hypoxia using HX4-PET imaging. FDG- and HX4-PET/CT images of 25 patients with NSCLC were coregistered. At a global tumor level, HX4 and FDG parameters were extracted from the gross tumor volume (GTV). The HX4 high-fraction (HX4-HF) and HX4 high-volume (HX4-HV) were defined using a tumor-to-blood ratio > 1.4. For FDG high-fraction (FDG-HF) and FDG high-volume (FDG-HV), a standardized uptake value (SUV) > 50% of SUVmax was used. We evaluated the spatial correlation between HX4 and FDG uptake within the tumor, to quantify the (mis)match between volumes with a high FDG and high HX4 uptake. At a tumor level, significant correlations were observed between FDG and HX4 parameters. For the primary GTV, the HX4-HF was three times smaller compared with the FDG-HF. In 53% of the primary lesions, less than 1 cm(3) of the HX4-HV was outside the FDG-HV; for 37%, this volume was 1.9 to 12 cm(3). Remarkably, a distinct uptake pattern was observed in 11%, with large hypoxic volumes localized outside the FDG-HV. Hypoxic tumor volumes are smaller than metabolic active volumes. Approximately half of the lesions showed a good spatial correlation between the PET tracers. In the other cases, a (partial) mismatch was observed. The addition of HX4-PET imaging has the potential to individualize patient treatment.

WE-G-BRD-06: Variation in Dynamic Positron Emission Tomography Imaging of Tumor Hypoxia in Early Stage Non-Small Cell Lung Cancer Patients Undergoing Stereotactic Body Radiotherapy

Purpose: Tumor hypoxia is correlated with treatment failure. To date, there are no published studies investigating hypoxia in non-small cell lung cancer (NSCLC) patients undergoing SBRT. We aim to use 18F-fluoromisonidazole (18F-FMISO) positron emission tomography (PET) imaging to non-invasively quantify the tumor hypoxic volume (HV), to elucidate potential roles of reoxygenation and tumor vascular response at high doses, and to identify an optimal prognostic imaging time-point. Methods: SBRT-eligible patients with NSCLC tumors >1cm were prospectively enrolled in an IRB-approved study. Computed Tomography and dynamic PET images (0–120min, 150–180min, and 210–240min post-injection) were acquired using a Siemens BiographmCT PET/CT scanner. 18F-FMISO PET was performed on a single patient at 3 different time points around a single SBRT delivery of 18 Gy and HVs were compared using a tumor-to-blood ratio (TBR)>1.2 and rate of influx (Ki)>0.0015 (Patlak). Results: Results from our first patient showed substantial temporal changes in HV following SBRT. Using a TBR threshold >1.2 and summed images 210–240min, the HVs were 19%, 31% and 13% of total tumor volume on day 0, 2 (48 hours post-SBRT), and 4 (96 hours post-SBRT). The absolute volume of hypoxia increased by nearly a factor of 2 after 18 Gy and then decreased almost to baseline 96 hours later. Selected imaging timepoints resulted in temporal changes in HV quantification obtained with TBR. Ki, calculated using 4-hour dynamic data, evaluated HVs as 22%, 75% and 21%, respectively. Conclusions: ith the results of only one patient, this novel pilot study highlights the potential benefit of 18F-FMISO PET imaging as results indicate substantial temporal changes in tumor HV post-SBRT. Analysis suggests that TBR is not a robust parameter for accurate HV quantification and heavily influenced by imaging timepoint selection. Kinetic modeling parameters are more sensitive and may aid in future treatment individualization based on patient-specific biological information.

Molecular Imaging of Tumor Hypoxia with Positron Emission Tomography

The problem of tumor hypoxia has been recognized and studied by the oncology community for over 60 years. From radiation and chemotherapy resistance to the increased risk of metastasis, low oxygen concentrations in tumors have caused patients with many types of tumors to respond poorly to conventional cancer therapies. It is clear that patients with high levels of tumor hypoxia have a poorer overall treatment response and that the magnitude of hypoxia is an important prognostic factor. As a result, the development of methods to measure tumor hypoxia using invasive and noninvasive techniques has become desirable to the clinical oncology community. A variety of imaging modalities have been established to visualize hypoxia in vivo. Positron emission tomography (PET) imaging, in particular, has played a key role for imaging tumor hypoxia because of the development of hypoxia-specific radiolabelled agents. Consequently, this technique is increasingly used in the clinic for a wide variety of cancer types. Following a broad overview of the complexity of tumor hypoxia and measurement techniques to date, this article will focus specifically on the accuracy and reproducibility of PET imaging to quantify tumor hypoxia. Despite numerous advances in the field of PET imaging for hypoxia, we continue to search for the ideal hypoxia tracer to both qualitatively and quantitatively define the tumor hypoxic volume in a clinical setting to optimize treatments and predict response in cancer patients.

Preclinical evaluation of parametric image reconstruction of [18F]FMISO PET: correlation with ex vivo immunohistochemistry

Compared to indirect methods, direct parametric image reconstruction (PIR) has the advantage of high quality and low statistical errors. However, it is not yet clear if this improvement in quality is beneficial for physiological quantification. This study aimed to evaluate direct PIR for the quantification of tumor hypoxia using the hypoxic fraction (HF) assessed from immunohistological data as a physiological reference. Sixteen mice with xenografted human squamous cell carcinomas were scanned with dynamic [18F]FMISO PET. Afterward, tumors were sliced and stained with H&E and the hypoxia marker pimonidazole. The hypoxic signal was segmented using k-means clustering and HF was specified as the ratio of the hypoxic area over the viable tumor area. The parametric Patlak slope images were obtained by indirect voxel-wise modeling on reconstructed images using filtered back projection and ordered-subset expectation maximization (OSEM) and by direct PIR (e.g., parametric-OSEM, POSEM). The mean and maximum Patlak slopes of the tumor area were investigated and compared with HF. POSEM resulted in generally higher correlations between slope and HF among the investigated methods. A strategy for the delineation of the hypoxic tumor volume based on thresholding parametric images at half maximum of the slope is recommended based on the results of this study.

Abstract SY42-02: Novel PET imaging in the clinic: Selecting patient cohorts and measuring early response

Abstract SY42-02: Novel PET imaging in the clinic: Selecting patient cohorts and measuring early response

P5-13-04: Changes in Phosphorylation Status at VEGFR2 and Basal Tumor Hypoxic Volume Assessed by Misonidazol (MISO) Positron Emission Tomography (PET/CT) as Potential Biomarkers for Predicting Response to Bevacizumab in Breast Cancer.

Abstract Background: To evaluate the expression of novel putative biomarkers as predictors of benefit from bevacizumab in stage II-III, previously untreated breast cancers (BC) patients (pts) in the context of a phase II, single-arm, multicenter and prospective clinical trial. To address this aim, we examined baseline and induced changes after a single bevacizumab administration as potential early predictors of response. Methods: Pts received a single infusion of bevacizumab (15 mg/kg) (C1) 3 weeks prior to the beginning of neoadjuvant chemotherapy consisting in 4 cycles of docetaxel (60 mg/mq), doxorubicin (50 mg/mq) and bevacizumab (15 mg/kg) every 21 days (C2-C5) following by surgery. Early assessment of tumor changes was performed by paired tumor-biopsies and MISO PET/CT before and 14–21 days after bevacizumab administration (C1). Biomarker expression was assessed by immunohistochemistry (IHC) (Ki67, CD31, CD31/Ki67, VEGFR2, pVEGFR2 [Y951]) on formalin-fixed, paraffin-embedded tissue before and after bevacizumab infusion (C1). MISO SUV and tumor volume depicted by PET were calculated. Pathological response on surgical specimens was assessed according to Miller/Payne classification. Pts with tumor reduction &amp;gt;90% were considered as best responders (G4-G5) whether tumor reduction &amp;lt;90% were considered as no responders. Association between pathological response, IHC and MISO biomarkers was analyzed using Mann-Whitney test. ROC curve was performed to test sensibility and specificity of the biomarker found significantly associated with response and its value as independent predictor was tested in the multivariate analysis using logistic regression. Results: This analysis was performed on the training set including 73 patients (49 yr, range 29–70). Twenty (27%) patients obtained best response (G4-G5) whether 50 (68%) were considered as no responder (G1-G2-G3). Response was associated with negative estrogen receptors expression (p=0.02) and high Ki67 basal and after C1 expression (p=0.009 and p=0.01). Six (54%) of triple negative tumors were responders (p=0.05). Interestingly, change in pVEGFR2 [Y951] staining induced by bevacizumab administration and basaline MISO tumor volume was found significantly associated with response (p=0.03 and 0.057). Decrease in the phosphorilation status of VEGFR2 (Y951) &amp;gt;70% yielded a receiver operating characteristic (ROC) curve area of 0.681 (95% CI: 0.536 — 0.825) with 84% sensitivity and 95% specificity. The positive and negative predictive values for this marker were 60% and 64%, respectively. The change in phosphorilation status of VEGFR2p remains a significant predictor biomarker of response in multivariate analysis (OR=0.9, IC%95 0.96−0.99, p=0.04) after adjusting for clinical-pathological characteristics. Conclusion: These findings underline the potential value of early decrease in phosphorilation status of VEGFR2 after bevacizumab infusion as predictive biomarker of response to anti-angiogenic therapy in breast cancer. Moreover, tumor hypoxic volume obtained by MISO might be associated with response. A validation set is warranted to confirm these findings. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-13-04.

Trans sodium crocetinate: functional neuroimaging studies in a hypoxic brain tumor

Intratumoral hypoxia is believed to be exhibited in high-grade gliomas. Trans sodium crocetinate (TSC) has been shown to increase oxygen diffusion to hypoxic tissues. In this research, the authors use oxygen-sensitive PET studies to evaluate the extent of hypoxia in vivo in a glioblastoma model and the effect of TSC on the baseline oxygenation of the tumor. The C6 glioma cells were stereotactically implanted in the right frontal region of rat brains. Formation of intracranial tumors was confirmed on MR imaging. Animals were injected with Copper(II) diacetyl-di(N4-methylthiosemicarbazone) (Cu-ATSM) and then either TSC or saline (6 rats each). Positron emission tomography imaging was performed, and relative uptake values were computed to determine oxygenation within the tumor and normal brain parenchyma. Additionally, TSC or saline was infused into the animals, and carbonic anhydrase 9 (CA9) and hypoxia-inducing factor-1α (HIF-1α) protein expression were measured 1 day afterward. On PET imaging, all glioblastoma tumors demonstrated a statistically significant decrease in uptake of Cu-ATSM compared with the contralateral cerebral hemisphere (p = 0.000002). The mean relative uptake value of the tumor was 3900 (range 2203-6836), and that of the contralateral brain tissue was 1017 (range 488-2304). The mean relative hypoxic tumor volume for the saline group and TSC group (6 rats each) was 1.01 ± 0.063 and 0.69 ± 0.062, respectively (mean ± SEM, p = 0.002). Infusion of TSC resulted in a 31% decrease in hypoxic volume. Immunoblot analysis revealed expression of HIF-1α and CA9 in all tumor specimens. Some glioblastomas exhibit hypoxia that is demonstrable on oxygen-specific PET imaging. It appears that TSC lessens intratumoral hypoxia on functional imaging. Further studies should explore relative hypoxia in glioblastoma and the potential therapeutic gains that can be achieved by lessening hypoxia during delivery of adjuvant treatment.

Planning study for available dose of hypoxic tumor volume using fluorine-18-labeled fluoromisonidazole positron emission tomography for treatment of the head and neck cancer

Purpose To investigate the feasibility of fluorine-18-labeled fluoromisonidazole positron emission tomography/computed tomography ( 18F-FMISO PET/CT)-guided intensity-modulated radiotherapy (IMRT) in dose escalation to attack the hypoxic volume of a tumor mass without increasing the normal tissue dose in head and neck cancer patients. Materials and methods Eight consecutive head and neck cancer patients underwent 18F-FMISO PET/CT simulation. Hypoxic tumor volume (HTV) was defined using a tumor-to-cerebellum ratio (T/C) of 1.3 as the threshold for 18F-FMISO PET/CT. Dose-escalation plans for treating HTVs using 18F-FMISO PET/CT-guided IMRT were performed for these patients. The standard plan was 72 Gy to the gross tumor volume (GTV) administered as 30 daily fractions of 2.4 Gy. In biologically optimized IMRT plans, the daily dose to the HTV ranged from 2.6 to 3.6 Gy. Dose–volume histograms (DVHs) were generated as part of each plan, and the results of planning were analyzed. Results Dose-escalation IMRT plans, delivering 30 daily doses of 2.6 Gy (total of 78 Gy) to the HTVs without increases in normal tissue doses, were feasible for six patients. Further acceptable dose escalation on HTV depended primarily on the primary tumor site and the extent of disease. Conclusions It was possible to dose escalate the HTV radiation to 78 Gy in six of eight head and neck cancer patients using 18F-FMISO PET/CT-guided IMRT.

Relationship between [18]Fluoroazomycin-Arabinoside (FAZA) Uptake and Hypoxia Markers in Head and Neck Squamous Cell Carcinomas (HNSCC)

To determine the relationship between circulating and tissue hypoxia markers to the hypoxic tumor volume (HTV) and the standard uptake values (SUV) as defined by FAZA-PET to image hypoxia in patients with HNSCC treated with chemoradiation on a prospective study.

The Influence of Changes in Tumor Hypoxia on Dose-Painting Treatment Plans Based on 18F-FMISO Positron Emission Tomography

To evaluate how changes in tumor hypoxia, according to serial fluorine-18-labeled fluoro-misonidazole (18F-FMISO) positron emission tomography (PET) imaging, affect the efficacy of intensity-modulated radiotherapy (IMRT) dose painting. Seven patients with head and neck cancers were imaged twice with FMISO PET, separated by 3 days, before radiotherapy. Intensity-modulated radiotherapy plans were designed, on the basis of the first FMISO scan, to deliver a boost dose of 14 Gy to the hypoxic volume, in addition to the 70-Gy prescription dose. The same plans were then applied to hypoxic volumes from the second FMISO scan, and the efficacy of dose painting evaluated by assessing coverage of the hypoxic volumes using Dmax, Dmin, Dmean, D95, and equivalent uniform dose (EUD). Similar hypoxic volumes were observed in the serial scans for 3 patients but dissimilar ones for the other 4. There was reduced coverage of hypoxic volumes of the second FMISO scan relative to that of the first scan (e.g., the average EUD decreased from 87 Gy to 80 Gy). The decrease was dependent on the similarity of the hypoxic volumes of the two scans (e.g., the average EUD decrease was approximately 4 Gy for patients with similar hypoxic volumes and approximately 12 Gy for patients with dissimilar ones). The changes in spatial distribution of tumor hypoxia, as detected in serial FMISO PET imaging, compromised the coverage of hypoxic tumor volumes achievable by dose-painting IMRT. However, dose painting always increased the EUD of the hypoxic volumes.

Risk assessment in high grade sarcoma patients during neoadjuvant chemotherapy using multiple tracer PET

20006 Background: Patients with high grade soft tissue sarcomas are treated with neoadjuvant chemotherapy. Sarcomas have biological features that may predict for poor outcome. Some of these features are tumor proliferation rate, level of tumor hypoxia, and upregulation of tumor drug resistance mechanisms. Methods: We have a group of specific PET imaging agents to quantify the level of activity of these tumor processes. Patients with soft tissue sarcomas receive [C-11]Thymidine (TdR) to assess cellular proliferation, [O-15] Water to quantify tumor blood flow and to serve as the input function for quantification of the other tracers, [C-11]Verapamil to assess drug resistance mechanism activity, and [F-18]Fluoromisonidazole) FMISO to quantify changes in tumor hypoxic volume in response to treatment. These studies are performed in a single PET imaging session prior to neoadjuvant chemotherapy, after the second of four cycles of therapy and in the week prior to resection. Results: An example of this complex study result, is demonstrated by a recent patient with a high grade soft tissue sarcoma. The tumor showed increased TdR uptake, a moderate hypoxic volume, and [C-11] verapamil uptake prior to initiation of neoadjuvant adriamycin based chemotherapy. After 2 cycles of therapy, there was a significant decrease in the maximum level and volume of TdR uptake and a large reduction in tumor hypoxic volume. Conclusions: These data would imply a high risk soft tissue sarcoma due the presence of increased cellular proliferation, a significant hypoxic volume and the absence of p-glycoprotein activity determined by the presence of [C-11]Verapamil uptake. However, early response is also suggested by the findings above. Patient outcome will be assessed and correlated with these tumor parameters to further understand what tumor biological risk factors can be quantified non-invasively and repeated throughout the clinical course in soft tissue sarcoma patients. Supported by NIH NCI PO1 42045–18 and S10 RR017229–01 [Table: see text] No significant financial relationships to disclose.

A novel approach to overcome hypoxic tumor resistance: Cu-ATSM-guided intensity-modulated radiation therapy

Purpose: Locoregional tumor control for locally advanced cancers with radiation therapy has been unsatisfactory. This is in part associated with the phenomenon of tumor hypoxia. Assessing hypoxia in human tumors has been difficult due to the lack of clinically noninvasive and reproducible methods. A recently developed positron emission tomography (PET) imaging-based hypoxia measurement technique which employs a Cu(II)-diacetyl-bis( N 4-methylthiosemicarbazone) (Cu-ATSM) tracer is of great interest. Oxygen electrode measurements in animal experiments have demonstrated a strong correlation between low tumor pO 2 and excess 60Cu-ATSM accumulation. Intensity-modulated radiation therapy (IMRT) allows selective targeting of tumor and sparing of normal tissues. In this study, we examined the feasibility of combining these novel technologies to develop hypoxia imaging (Cu-ATSM)-guided IMRT, which may potentially deliver higher dose of radiation to the hypoxic tumor subvolume to overcome inherent hypoxia-induced radioresistance without compromising normal tissue sparing. Methods and Materials: A custom-designed anthropomorphic head phantom containing computed tomography (CT) and positron emitting tomography (PET) visible targets consisting of plastic balls and rods distributed throughout the “cranium” was fabricated to assess the spatial accuracy of target volume mapping after multimodality image coregistration. For head-and-neck cancer patients, a CT and PET imaging fiducial marker coregistration system was integrated into the thermoplastic immobilization head mask with four CT and PET compatible markers to assist image fusion on a Voxel-Q treatment-planning computer. This system was implemented on head-and-neck cancer patients, and the gross tumor volume (GTV) was delineated based on physical and radiologic findings. Within GTV, regions with a 60Cu-ATSM uptake twice that of contralateral normal neck muscle were operationally designated as ATSM-avid or hypoxic tumor volume ( hGTV) for this feasibility study. These target volumes along with other normal organs contours were defined and transferred to an inverse planning computer (Corvus, NOMOS) to create a hypoxia imaging-guided IMRT treatment plan. Results: A study of the accuracy of target volume mapping showed that the spatial fidelity and imaging distortion after CT and PET image coregistration and fusion were within 2 mm in phantom study. Using fiducial markers to assist CT/PET imaging fusion in patients with carcinoma of the head-and-neck area, a heterogeneous distribution of 60Cu-ATSM within the GTV illustrated the success of 60Cu-ATSM PET to select an ATSM-avid or hypoxic tumor subvolume ( hGTV). We further demonstrated the feasibility of Cu-ATSM-guided IMRT by showing an example in which radiation dose to the hGTV could be escalated without compromising normal tissue (parotid glands and spinal cord) sparing. The plan delivers 80 Gy in 35 fractions to the ATSM-avid tumor subvolume and the GTV simultaneously receives 70 Gy in 35 fractions while more than one-half of the parotid glands are spared to less than 30 Gy. Conclusion: We demonstrated the feasibility of a novel Cu-ATSM-guided IMRT approach through coregistering hypoxia 60Cu-ATSM PET to the corresponding CT images for IMRT planning. Future investigation is needed to establish a clinical-pathologic correlation between 60Cu-ATSM retention and radiation curability, to understand tumor re-oxygenation kinetics, and tumor target uncertainty during a course of radiation therapy before implementing this therapeutic approach to patients with locally advanced tumor.